FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Discuss the role of bone morphogenic proteins in vascular calcification.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.Decrease phosphate( by decreasing po42- tubular reabsorption) , decrease PTH( parathyroid gland) and decrease active vitamin D
Heart – lvh and cardiovascular calcification ( smooth muscle change into osteoblast)
2 Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Bone- associated with adynamic bone disease/low turnover disease however it can be associated with vascular calcification
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
regulators- vitamin d and pth. Osteocalcin expression by the BGLAP gene and
production are directly stimulated by vitamin D through a
vitamin-D-responsive element located in the promoter
region of BGLAP. Parathyroid hormone also stimulates
osteocalcin production through its binding to the receptor
PTH1R and activation of the cAMP-dependent proteinkinase-A intracellular signalling pathway
2.Carboylated form of osteoclacin:
Regulate bone mineralization
changing the size and shape of the hydroxyapatite.
Potential modulator of osteoblast/osteoclast activities
Uncarboylateed form
increased insulin resistance/secretion- atherosclerosis and soft tissue calcification
Vitamin D Deficiency and LVH
Discuss the role of bone morphogenic proteins in vascular calcification. ( they are cytokines that work via the intracelluar messaging pathway and have scope for differentiation.
BMP2 stimulates stimulate osteoregulatory gene MSK2 and that leads to increase phosphate reabsoprtion via type 3 na dependent phosphate transporter. Furthermore, BMP7 inhibits vascular calcification in experimental atherosclerosis112 and adynamic bone lesions and vascular calcification in experimental
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.A. FGF23-klotko adaptive response:
Parathyroid gland & the kidney; inhibit PTH secretion and enhance phosphorus excretion from the kidney.
B. FGF23-klotho maladaptive response:
Heart; Left Ventricular Hypertrophy
Kidney; High FGF23 but absence of renal klotho (resistant to FGF23 effect)
Parathyroid gland; PTH continue to rise in advanced CKD despite high FGF23 (resistance to FGF23 as a result of loss of klotho)
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Sclerostin is a soluble Wnt inhibitors,
Wnt signalling pathways play a key part in many diverse biological processes, such as cell proliferation, growth, migration, and differentiation
1.Bone:
Wnt-catenin pathway inhibitor
Suppress bone morphogenic proteins.
Adynamic bone disease
2.Cardiovascular system:
Atherosclerosis
Apoptosis of vascular smooth muscle cells
Valvular, vascular calcification and Calciphylaxis
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.Discuss the role of bone morphogenic proteins in vascular calcification.
PTH and Vitamin D
2.Carboylated form of osteoclacin:
Regulate bone mineralization
Changing the size and shape of the hydroxyapatite.
Potential modulator of osteoblast/osteoclast activities
3.Uncarboylated form”
CKD and vitamin K deficiency
Negative effect on insulin secretion and sensitivity, adipose tissue
Risk of cardiovascular diseases.
Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 stimulates the osteo-regulatory gene MSX2 and enhances phosphate uptake .
BMP2 expression is increased in arterial calcification
BMP7 over expression suppresses vascular calcification in experimental animal models.
BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
in renal disease BMP7 expression is significantly reduced in renal tissue and circulatory BMP7 concentrations are low.
1- FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.A. FGF23-klotko adaptive response:
Parathyroid gland & the kidney; inhibit PTH secretion and enhance phosphorus excretion from the kidney.
B. FGF23-klotho maladaptive response:
Heart; Left Ventricular Hypertrophy
Kidney; High FGF23 but absence of renal klotho (resistant to FGF23 effect)
Parathyroid gland; PTH continue to rise in advanced CKD despite high FGF23 (resistance to FGF23 as a result of loss of klotho)
2- Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.Wnt/ B-catenin is intracellular pathway which regulate osteoblastic activity, when wnt is activated, bone is formed, and inhibited, the bone formation is inhibited. Sclerostin is a soluble inhibitor of wnt. Sclerostin is increased in CKD patients, but unknown due to increase secretion or due to decreased clearance. Increased sclerostin in ckd decreases bone formation, precipitating adynamic bone disease.
high sclerostin levels with seemingly increased vascular calcification rate and severity, as wnt regulates apoptosis of vascular smooth muscles cells.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.1.Osteocalcin is stimulated by
PTH and Vitamin D
2.Carboylated form of osteoclacin:
Regulate bone mineralization
changing the size and shape of the hydroxyapatite.
Potential modulator of osteoblast/osteoclast activities
3.Uncarboylated form”
CKD and vitamin K deficiency
Negative effect on insulin secretion and sensitivity, adipose tissue
risk of cardiovascular diseases.
Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 stimulates the osteo-regulatory gene MSX2 and enhances phosphate uptake .
BMP2 expression is increased in arterial calcification
BMP7 over expression suppresses vascular calcification in experimental animal models.
BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
in renal disease BMP7 expression is significantly reduced in renal tissue and circulatory BMP7 concentrations are low.
FGF-23 and Klotho have separate and related effects on bone. FGF-23 starts to increase in the early stages of CKD, most probably to compensate for the decrease in phosphate excretion. Klotho and FGF23 have a lowering effect on PTH as well. In the early stages, elevation of FGF23 coincides with low phosphate which may reflect maladaptation.
Sclerostin, which is an important Wnt inhibitor. Wnt signaling is an important pathway important for bone mineralization. Sclerostin is a target of treatment (by use of Rmosuzumab). WNT signaling also has an important role in human atherosclerosis.
Osteocalcin is controlled by both vitamin D and PTH. The uncarboxylated form is the one that constitutes the circulating portion of osteocalcin. The uncarboxylated form increased insulin sensitivity and prevented adiposity in mice.
Bone morphogenic proteins like osteogenin, BMP2, and BMP7. Especially BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake through upreulation of type 3 sodium-dependent phosphate cotransporter in vascular smooth muscle calcification. BMP2 is considered an important induction factor for calcification
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.The physiological role of FGF23 is to maintain balance of phosphorus and vitamin D; its concentration increases as the glomerular filtration rate falls, because the kidney has a key role in excreting excess phosphate.Other physiological actions of FGF23 are to reduce production and secretion of parathyroid hormone, and interference with metabolism of vitamin D, leading to a fall in the concentration of 1,25-dihydroxycholecalciferol (the active form of vitamin D).
Direct FGF23 toxicity would be directed toward the cardiovascular system (left ventricular hypertrophy & calcification of the arterial wall). Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.sclerostin showed strong negative associations with parameters of bone turnover, pointing towards a role of high sclerostin concentrations in induction of adynamic bone disease, or vice versa.
Wnt signalling has a crucial role in human atherosclerosis, and therefore increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with this process. In view of the crucial role of apoptosis of vascular smooth-muscle cells in vascular calcification, circulating Wnt inhibitors also affect this process.
Sclerostin expression has also been shown in calcifying vascular smooth muscle cells& in patients with calciphylaxis. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.It is regulated by the two major mineral and bone-controlling hormones, vitamin D and parathyroid hormone. Osteocalcin expression by the BGLAP gene and production are directly stimulated by vitamin D through a vitamin-D-responsive element located in the promoter region of BGLAP. Parathyroid hormone also stimulates osteocalcin production through its binding to the receptor PTH1R and activation of the cAMP-dependent protein- kinase-A intracellular signalling pathway.
Under conditions of normal kidney function and the absence of vitamin K de ciency, the proportion of uncarboxylated osteocalcin is low, stimulating insulin secretion and improving insulin sensitivity and energy handling. In the setting of chronic kidney disease or vitamin K de ciency, the amount of uncarboxylated osteocalcin increases, and as such negatively affects insulin secretion and sensitivity, promoting cardiovascular disease. Discuss the role of bone morphogenic proteins in vascular calcification.CKD could be a disorder of BMP2 and BMP7 dysregulation, potentially involved in the pathological processes of calci cation in orthotopic and ectopic tissues.
BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake through upregulation of the type III sodium- dependentphosphateco-transporter in vascular smooth- muscle calcification.
BMP2 expression is increased in the vessel wall in response to inflammation,and these calcifying effects are inhibited by MGP (which binds to BMP2) and SMAD6.
BMP2 is thus regarded as an important induction factor of calcification. Clinically, serum concentrations of BMP2 are increased in patients with CKD and are positively associated with vascular sitffness.
BMP7 represents an inhibitor of calcification possibly implicated in bone and vascular disease. In different experimental models of renal disease, a signi cant reduction of BMP7 expression occurs in renal tissue, and circulating BMP7 concentrations are reported to be low.
Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins have a role in several clinical disorders ranging from vascular calcification to obesity, diabetes, and cancer.
Bone morphogenetic proteins can be generally regarded as local (auto or paracrine) modulators of the inflamma- tory effects of transforming growth factor β.
some bone morphogenetic proteins seem to be linked with the CKD-MBD syndrome.
In particular, BMP2 and BMP7 have both been extensively studied in relation to experimental vascular calcification.
BMP2 expression is increased in the vessel wall in response to inflammation,and these calcifying effects are inhibited by MGP (which binds to BMP2) and SMAD6.
BMP2 is thus regarded as an important induction factor of calcification.
Clinically, serum concentrations of BMP2 are increased in patients with CKD and are positively associated with vascular stiffness.
BMP7 promotes the phenotype of vascular smooth-muscle calcification, and thus represents an inhibitor of calcification possibly implicated in bone and vascular disease.
BMP2 and BMP7 have been suggested to have anabolic effects through interaction with SOST and DKK1 in bone and to protect podocytes from profibrotic stimuli.Besides these local cytokine- like effects, BMP2 and BMP7 might have systemic effects in view of their reported association with calciprotein particles and arterial stiffness in patients with CKD.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands? 1- adaptive response:
inhibit PTH secretion
enhance Pi excretion
2- maladaptive response:
Heart: LVH
Kidney: High FGF23 + absence of renal klotho (resistance)
Parathyroid gland: PTH continue to rise in advanced CKD+high FGF23 (resistance)
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system. 1.Bone:
Wnt-catenin pathway inhibitor
Suppress bone morphogenic proteins.
Adynamic bone disease
2.Cardiovascular system:
Atherosclerosis
Apoptosis of vascular smooth muscle cells
Valvular, vascular calcification and Calciphylaxis
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation. 1.Osteocalcin is stimulated by
PTH and Vitamin D
2.Carboylated form of osteoclacin:
Regulate bone mineralization
changing the size and shape of the hydroxyapatite.
Potential modulator of osteoblast/osteoclast activities
3.Uncarboylated form”
CKD and vitamin K deficiency
Negative effect on insulin secretion and sensitivity, adipose tissue
risk of cardiovascular diseases.
IV.Discuss the role of bone morphogenic proteins in vascular calcification. 1.BMP2
Active MSX2; regulator of genes in the bone
Decrease expression of the vascular smooth muscle cell markers, which promotes the osteoblast-like phenotype.
Enhance Pi uptake by upregulation of type III Na/Pi co-transporter in vascular smooth muscle calcification.
BMP2 expression is increase in the vessel wall, Promotes vascular stiffness.
2.BMP7:
Inhibitor of vascular calcification:
by promoting vascular smooth muscle cell phenotype
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin, also known as bone gla protein, is a 6 kD calcium-binding bone-matrix protein produced by osteoblasts, and is one of the most abundant non-collagen proteins in bone. It is regulated by the two major mineral and bone-controlling hormones, vitamin D and parathyroid hormone.
No receptor for osteocalcin has been identified, but the protein might modulate activities of the G-coupled protein receptor GPRC6A, which is widely expressed.Osteocalcin acts as a regulator of bone mineralisation, affecting hydroxyapatite size and shape, and is a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form.
Uncarboxylated (or under- carboxylated) forms of osteocalcin that are not bound to hydroxyapatite are released into the bloodstream, where they accumulate with fragments derived from direct proteolysis of osteocalcin after bone resorption, to constitute circulating osteocalcin.
Concentrations of circulating uncarboxylated forms of osteocalcin are affected by vitamin K status and directly by the degree of bone remodelling, as reported in both patients with CKD and those undergoing haemodialysis, for whom circulating concentration of total osteocalcin is positively correlated with histological parameters of bone remodelling.
There’s an inverse link between total osteocalcin concentrations in serum samples and glycaemia, glucose metabolism, and measures of adiposity.
The complex association between vitamin K status and osteocalcin could be another explanation. Vitamin K supplementation decreases concentrations of uncarboxylated forms of osteocalcin,but has shown variable effects on glucose metabolism in the small number of human studies reported,and no solid data about the effect the of oral vitamin K antagonist, warfarin, on energy metabolism are available.
Schafer and colleagues reported that parathyroid hormone increased and alendronate reduced concentrations of uncarboxylated osteocalcin, and that these changes were associated with changes in bodyweight, fat mass, and serum concentrations of adiponectin, but the investigators did not find linkage between changes in uncarboxylated osteocalcin and changes in concentrations of glucose and insulin.
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Wnt signalling is of great importance for skeletal health. Besides being an inhibitor of the Wnt-catenin pathway ,sclerostin acts by other modes—eg, suppressive effects on bone morphogenic proteins.The clinical relevance of Wnt signalling for bone can easily be established in human disorders such as sclerostosis and Van Buchem’s disease, and in genetically modified rodent models.Although reduced activity of sclerostin and DKK1 leads to increased bone mass and strength, the opposite occurs in animal models with overexpression of both sclerostin and Dkk1.In addition to direct effects of sclerostin on local Wnt pathways, the effects of parathyroid hormone on bone also depend on sclerostin activity. All these data point to the importance of balanced activity of Wnt signalling for bone health. In CKD, this activity is probably disturbed because of typically increased circulating concentrations of sclerostin.However, the effects of these increased concentrations are not straightforward; on the one hand, reduced osteocytic Wnt-β-catenin signalling was an early finding during the course of experimental CKD-MBD,but on the other, activity of Wnt-catenin pathways is increased in monocytes from patients with CKD.
Besides affecting bone metabolism, Wnt signalling has a crucial role in human atherosclerosis,and therefore increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with this process.
Additionally, findings from experimental studies have shown a wide range of effects of Wnt activation on cell function for vascular smooth muscle, including protection against apoptosis.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
The physiological role of FGF23 is to maintain balance of phosphorus and vitamin D; its concentration increases as the glomerular filtration rate falls, because the kidney has a key role in excreting excess phosphate. Reduced ultrafiltration and excretion of phosphate due to a decreased glomerular filtration rate is balanced by decreased tubular reabsorption of phosphate due to the action of FGF23, which is an important physiological homoeostatic mechanism, tending to keep plasma concentrations of phosphate close to normal. Other physiological actions of FGF23 are to reduce production and secretion of parathyroid hormone, and interference with metabolism of vitamin D, leading to a fall in the concentration of 1,25-dihydroxycholecalciferol (the active form of vitamin D).Possibly related to the effect of FGF23 on activation of vitamin D are intriguing clinical and experimental findings that point to an important role of calcium as an inducer of FGF23 secretion.This suggested role of calcium possibly explains the lack of FGF23-lowering potency of therapy with calcium-based phosphatebinder. early-stage CKD, however, increased concentrations of FGF23 coincide with slight hypophosphataemia, suggesting that this increase is maladaptive, due to an unidentified CKD- related factor.Another argument for maladaptive increments of FGF23 comes from the non-consistent effects of oral phosphate-binding therapy on FGF23 concentrations, even when phosphorus uptake or plasma concentrations are adequately reduced.An additional reason to assume that CKD itself, separate from phosphate balance or concentrations, induces FGF23 is the finding that after kidney transplantation, FGF23 concentrations fall for several months, despite pronounced hypo- phosphataemia in many patients.At longer post- transplantation follow-up, FGF23 is positively associated with phosphate concentration again, suggesting disappearance of the maladaptive increase with time.In further investigations of the effects of CKD (and not phosphate concentrations) on FGF23, almost all circulating FGF23 was intact in patients undergoing peritoneal dialysis,by contrast with healthy people.This finding suggests that CKD inhibits FGF23 catabolism.
However, besides being maladaptive (especially in early stages of CKD), some evidence suggests that FGF23 concentrations rise because of a relative resistance to its renal effects, possibly due to downregulation of tissue α-klotho, a cofactor for FGF23 signalling.
Because the leading cause of morbidity and mortality in CKD is cardiovascular disease, the obvious site for direct FGF23 toxicity would be the cardiovascular system. Indeed, as for mortality, increased prevalence of left ventricular hypertrophy is strongly associated with increased FGF23 concentrations.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.First the adaptive mechanism of FGF23 Kolotho is taking place early in CKD which is newly discovered becuase of that there is no hyperphophatemia in early CKD stages because FGF23 is decrease reabsorbtion of phophate in the kidney but with advanced CKD the FGF 23 loss the adaptive mechanism and lead to hyperphophatemia with increase in PTH level and both of them will leads to LVH and incresae the cardiovascular calcification .
FGF23 is affecting multiple organs and can leads to increase the cytokines and inflanmatory response in the body .
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.As we all know that wint bathway is for bone formation and scelerostin is inhibit wibt bathway and inhibits bone formation . In case of osteoporosis the patient will have high sclerostin level with no bone formation and loss of balance between bone formation and bone resorption which leads to osteoporosis .
It has been known that sclerostin increased in CKD patient whether becuse of increased secretion or decrease excretion not clear.High sclerostin levels with seemingly increased vascular calcification rate and severity,as wnt regulates apoptosis of vascular sm.cells.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.osteocalcin is calcium binding bone matrix protein, produced by osteoblasts under control of vit D and PTH. It is a regulator of bone mineralization
It also acts as a potential modulator of osteoblasts and osteoclast activities through its vitK dependant gamma carboxylated form.
in CKD stage 3 to5 the level of. decraboxilated level to osteoclastin is high and this will affect the miniralization ,on the other hans as this osteocalstin is decarboxliated to active form under Vit K ,for that warfarin increase the uncarboxilated osteoclastin .
Discuss the role of bone morphogenic proteins in vascular calcification.
The BMPs are severla protiends which belongs to TGF B and they has a majour role in vascular calcifications speciaaly the BMP 2 AND BMP7 .
BMP2enhance Pi vesseles uptake while BMP7 IS a good type of protein which is decrease with advanced CKD and this protein had a good effect which is decrease the vascular calcification and has anti fibrotic effects
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on the kidney, heart, and parathyroid glands.
In early CKD stages, an increase of FGF23 with slight hypophosphatemia, due to unidentified CKD-related factors.
Non-consistent effects of oral phosphate-binding binder on FGF23 concentration.
CKD-induces FGF23.
Post-transplant, FGF23 is positively associated with phosphate levels.
The local mechanism in bone (non-phosphate related).
Wnt inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and the cardiovascular system.
Sclerostin has a suppressive effect on bone morphogenic proteins.
An increased sclerostin level decreases bone mass and strength.
Sclerostin indirectly affects the effect of PTH on bone.
Scleostin has a crucial effect on atherosclerosis and vascular calcification.
Romosozumab; an anti-sclerostin antibody, can increase bone mineral density in postmenopausal osteoporosis, and might induce new methods to improve sclerostin-induced disturbance in Wnt signaling in CKD.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Controlled by vitD and PTH.
It is a regulator of bone mineralization by affecting hydroxyapatite size and shape.
It also acts as a potential modulator of osteoblasts and osteoclast activities through its vitK dependant gamma carboxylated form.
In CKD stages 3-5, the ratio of uncarboxylated to total osteocalcin was found to be high.
Warfarin was found to increase uncarboxylated osteocalcin, and vit K associated with carboxylated osteocalcin.
Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 stimulates the osteoregulatory gene MSX2, and enhances Pi intake through upregulation of the type III sodium dependant Pi co-transporter in vascular smooth muscle calcification.
BMP2 concentration increases with inflammation and is inhibited by MGP which binds to BMP2, so BMP2 is considered as an induction factor for calcification and increases with advances in CKD stages with resultant vascular stiffness.
BMP7 is an inhibitor of calcification.
BMP7 levels decrease with advanced levels of CKD stages.
1-FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
Adaptive effect on kideny and parathyroid gland in combination with koltho have increase po4 excretion and decrease pth secretion
Mal adaptive effect
In advanced kidney disease will loss of koltho so fgf23 loss phosphaturic effect
Increase pth
Lead to ventricular hypertrophy and accelerate atherosclerosis and vascular calcification.
2-Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
sclerostin inhibits the wnt signaling pathway, sclerostin decreases bone formation and increases bone resorption, resulting in a reduction in bone density and oesteoprosis
recent research indicates that sclerostin may contribute to the pathogenesis of cardiovascular disease. sclerostin has been detected in vascular tissue, and studies have shown that patients with cardiovascular disease have elevated sclerostin levels. this may be due to the wnt signaling pathway’s role in vascular calcification, which is believed to contribute to the development of atherosclerosis and other cardiovascular diseases. sclerostin may promote vascular calcification by inhibiting the wnt signaling pathway in vascular smooth muscle cells.
3-Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Main regulator for secretion of osteocalcin from oesteoblast are vit d and pth .
The carboxylated form vit k dependant so any affection on vit k reflected on its carboxylation and regulate bone mineralization changing the size and shape of the hydroxyapatite.Potential modulator of osteoblast/osteoclast activities
4-Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 and BMP7 have both been extensively studied in relation to experimental vascular calcification.
BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake.
The BMP2 expression is increased in arterial calcification, and BMP7 overexpression suppresses vascular calcification in experimental animal models.
BMP2 and BMP7 may have a role in vascular calcification, either directly or through the modulation of other factors in the calcification process.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands. Kidney adaptive Fgf-23 decreases tubular phosphorus reabsorption, attenuate hyperphosphatemia due to decreased GFR. 2- Decrease PTH, Decrease vit D Maladapative In early stages of ckd, increased FGF-23 can cause hyphosphatemia 2- after kidney transplantation there is always hyperphosphatemia, but FGF-23 drop over several months BONE There is increase in expression of FGF-23 by osteocytes in early stages of CKD, due to disturbance between regulators. Heart FGF-23 is associated with increased CVS mortality and morbidity 2ry to left vent, hypertrophy and vascular calcification
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.Wnt/ B-catenin is intracellular pathway which regulate osteoblastic activity, when wnt is activated, bone is formed, and inhibited, the bone formation is inhibited.
Sclerostin is a soluble inhibitor of wnt.
Sclerostin is increased in CKD patients, but unknown due to increase secretion or due to decreased clearance.
Increased sclerostin in ckd decreases bone formation, precipitating adynamic bone disease.
high sclerostin levels with seemingly increased vascular calcification rate and severity,as wnt regulates apoptosis of vascular sm.cells Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.osteocalcin is calcium binding bone matrix protein, produced by osteoblasts under control of vit D and PTH. It has 2 forms carboxylated which is attached to hydroxyapatite and uncarboxylated form which circulates in the serum and account for 50% of total osteocalcin. the carboxylation is vit K dependent so it is affected by factors affecting vit k level and vit k antagoinists like warfarin
in ckd patient the uncarboxylate osteocalcin ratio is increased
unfractioned form in animal increase insulin sensitivity and secretion and protect from adiposity Discuss the role of bone morphogenic proteins in vascular calcificationBMPs are member of the TGF-β superfamily and includes at least 30 proteins They have a wide group of functions from vascular calcification to obesity. BMP2 and BMP 7 are associated vascular calcification,
I.FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
A. FGF23-klotko adaptive response:
Parathyroid gland & the kidney; inhibit PTH secretion and enhance Pi excretion from the kidney.
B. FGF23-klotho maladaptive response:
Heart; Left Ventricular Hypertrophy
Kidney; High FGF23 but absence of renal klotho (resistant to FGF23 effect)
Parathyroid gland; PTH continue to rise in advanced CKD despite high FGF23 (resistance to FGF23 as a result of loss of klotho)
II.Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system. 1.Bone:
Wnt-catenin pathway inhibitor
Suppress bone morphogenic proteins.
Decrease activity may results in increased bone mass and strength.
Adynamic bone disease
2.Cardiovascular system:
Atherosclerosis
Apoptosis of vascular smooth muscle cells
Valvular calcification
Vascular calcification
Calciphylaxis
III. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation. 1.Regulators of osteocalcin; osteocalcin is stimulated by
PTH
Vitamin D
2.Carboylated (Vitamin K dependent) form of osteoclacin:
Regulate bone mineralization changing the size and shape of the hydroxyapatite.
Potential modulator of osteoblast/osteoclast activities
3.Uncarboylated form e.g., CKD, vitamin K deficiency:
In these conditions high levels of carbonylated osteocalcin may lead to negative effect on insulin secretion and sensitivity, adipose tissue, risk of cardiovascular diseases.
IV.Discuss the role of bone morphogenic proteins in vascular calcification. 1.Bone morphogenetic protein 2(BMP2)
Active MSX2; regulator of genes in the bone
Decrease expression of the vascular smooth muscle cell markers, which promotes the osteoblast-like phenotype.
Enhance Pi uptake by upregulation of type III Na/Pi co-transporter in vascular smooth muscle calcification.
BMP2 expression is increase in the vessel wall.
Promotes vascular stiffness.
2.Bone morphogenic protein 7(BMP7):
Inhibitor of vascular calcification by promoting vascular smooth muscle cell phenotype
**Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
The mean regulator of osteocalcin are vitamin D through vitamin D responsive elements in the BGLAP gene and PTH through PTH1R, it secreted from osteoblast
The carboxylation affected by vitamin K status and by histological parameters of bone remodeling, it causes increase insulin secretion and sensitivity
Also increase in ckd, warfarin treatment increase uncarboxylated osteocalcin and decrease carboxylated osteocalcin
**Discuss the role of bone morphogenic proteins in vascular calcification.
Ranging from vascular calcification to obesity, diabetes and cancer, it can be regarded as cytokines with growth and differentiation properties, as local autocrine or paracrine modulators of inflammatory effects of TGF B,
BMP2 associated with vascular stiffness where as BMP7 an inhibitor of calcification
Both BMP2 and BMP7 has anabolic effects through interaction with SOSTand DKK1 in the bone and protect podocyte from profibrotic stimuli in addition to the local cytokines like effects.
**FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
It lead to increase phosphaturia, interfere with the metabolism of vitamin D lead to decrease calcitriol, it decrease the production and the secretion of PTH,
It effects on the heart lead to the left ventricular hypertrophy, vascular calcification and endothelial dysfunction
It also has antioxidants, vasoprotective, anticalcifying, phosphaturia
**Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system
It causes suppressive effects on bone morphogenic protein
It increase bone mass and strength
It has a role in atherosclerosis, causes vascular calcification, calcified aortic valve, it has an effect on calciphylaxis and also in Adynamic bone disease negative association of sclerostin on bone turnover, in addition to the negative effects on PTH
1. FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
The initial PO4 retention in CKD leads to increased secretion of FGF23, the latter is phosphaturic hormone (via inhibiting reabsorption of PO4 in PCT), but as CKD progresses FGF23 keep rising leading to inhibition of 1,and 25 hydroxylation if vitamin, and consequently increased secrion of PTH from parathyroid gland.
There is a link between elevated FGF-23 levels and multiple cardiovascular outcomes, including hypertension, left ventricular hypertrophy and cardiovascular events and mortality.
2. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Sclerostin inhibits the Wnt signaling pathway, which promotes bone development. By inhibiting this pathway, sclerostin decreases bone formation and increases bone resorption, resulting in a reduction in bone density. This is believed to contribute to the development of osteoporosis and other bone disorders.
Recent research indicates that sclerostin may contribute to the pathogenesis of cardiovascular disease. Sclerostin has been detected in vascular tissue, and studies have shown that patients with cardiovascular disease have elevated sclerostin levels. This may be due to the Wnt signaling pathway’s role in vascular calcification, which is believed to contribute to the development of atherosclerosis and other cardiovascular diseases. Sclerostin may promote vascular calcification by inhibiting the Wnt signaling pathway in vascular smooth muscle cells, as hypothesized. 3. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
*.vitamin D:
Vitamin D is an important osteocalcin secretion and carboxylation regulator. Vitamin D deficiency is associated with decreased osteocalcin levels, whereas supplementation with vitamin D can increase osteocalcin production. This is believed to be because vitamin D promotes the differentiation of osteoblasts, resulting in increased osteocalcin secretion.
* morphogenetic protein 2
BMP-2 is an essential growth factor for bone formation and remodeling. Studies have demonstrated that BMP-2 stimulates osteocalcin secretion and carboxylation by promoting osteoblast differentiation and increasing osteocalcin expression.
*insulin:
Insulin is another molecule capable of regulating the secretion and carboxylation of osteocalcin. It has been demonstrated that insulin stimulates osteoblast proliferation and differentiation, resulting in increased osteocalcin production. Additionally, insulin promotes the carboxylation of osteocalcin, which is believed to increase its bone mineralization-promoting activity.
4. Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 increases phosphate absorption through upregulation of the type III sodium-dependent phosphate co-transporter in vascular smooth-muscle calcification and the osteoregulatory gene MSX2. Inflammation increases vessel wall BMP2 expression, which inhibits calcification by way of MGP and SMAD6.
BMP2 induces calcification, and CKD patients had higher serum concentrations of BMP2 and stiffer blood vessels. BMP2 is associated with decreased expression of smooth-muscle cell markers in vascular smooth-muscle calcification, which promotes the osteoblastic-like phenotype. In contrast, BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
In renal disease models, BMP7 expression in renal tissue and BMP7 concentrations in the blood are significantly diminished. In experimental atherosclerosis, CKD, metabolic syndrome, and adynamic bone lesions, BMP7 also prevents vascular calcification.
BMP2 and BMP7 may protect podocytes from profibrotic stimuli and have metabolic interactions with SOST and DKK1 in bone.
BMP2 and BMP7’s association with calciprotein particles and arterial stiffness in CKD patients suggests systemic implications beyond these local cytokine-like effects.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
FGF23 is a bone-derived (osteoblasts and osteoclasts) hormone that suppresses phosphate reabsorption and Vitamin D.
In the kidney it acts on the the proximal and distal convulated tubules:
in the proximal tubules it inhibits phosphate re-uptake and expression of 1-alpha-hydroxylase
in the distal tubules , it increases the re-absorption of calcium and sodium
The discovery of this molecule has led to changes in the Trade-Off Theory which results in the development of Secondary Hyperparathyroidism/CKD-MBD
Findings from previous studies demonstrated an association of FGF23 and events related to mortality, cardiovascular disease and inflammation
In the early stages of CKD, the FGF23-Klotho pathway is adaptive, and it helps to maintain phosphate homeostasis by promoting urinary excretion of phosphate through decreased expression of the sodium-phosphate cotransporter in the proximal tubules of the kidney. This helps to reduce the risk of hyperphosphatemia, which can lead to cardiovascular complications in patients with CKD. Additionally, FGF23 stimulates the production and secretion of parathyroid hormone (PTH) by the parathyroid glands, which helps to maintain physiological levels of calcium in the blood.
In the later stages of CKD, however, prolonged activation of the FGF23-Klotho pathway can have maladaptive effects on the kidneys, heart, and parathyroid glands. FGF23 levels may become excessively elevated, leading to hypophosphatemia and loss of bone mineral density, and this can result in the development of osteomalacia and fractures. FGF23 may also contribute to the development of left ventricular hypertrophy and cardiovascular disease, as well as vascular calcification, which can increase the risk of cardiovascular events. Furthermore, chronic stimulation of the parathyroid glands by FGF23 can lead to the development of secondary hyperparathyroidism, which can further worsen CKD and contribute to bone and mineral disorders.
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Sclerostin is a soluble inhibitor of the Wnt signaling pathway that is expressed by osteocytes in bone. It plays a key role in the regulation of bone remodeling, and its levels are known to be altered in various bone and cardiovascular diseases. The effects of sclerostin on bone and cardiovascular disease are presumed to be as follows:
1. Effects on bone:
Sclerostin inhibits the Wnt signaling pathway, which is responsible for promoting bone formation. By inhibiting this pathway, sclerostin reduces bone formation and promotes bone resorption, leading to a decrease in bone density. This is thought to play a role in the pathogenesis of osteoporosis and other bone disorders. Anti-sclerostin antibodies have been developed as a potential treatment for osteoporosis, with initial studies showing promising results in increasing bone mineral density.
2. Effects on cardiovascular disease:
Recent studies have suggested that sclerostin may play a role in the pathogenesis of cardiovascular disease. Sclerostin has been shown to be present in vascular tissue, and studies have demonstrated that sclerostin levels are elevated in patients with cardiovascular disease. This may be due to the role of the Wnt signaling pathway in vascular calcification, which is thought to contribute to the development of atherosclerosis and other cardiovascular diseases. It has been suggested that sclerostin may promote vascular calcification by inhibiting the Wnt signaling pathway in vascular smooth muscle cells.
In summary, sclerostin, a Wnt inhibitor, plays a key role in bone remodeling and is involved in the pathogenesis of various bone disorders. Additionally, sclerostin has been implicated in the development of cardiovascular disease, with elevated levels associated with vascular calcification. Treatments targeting sclerostin inhibition are being developed as potential therapies for these conditions.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin is a calcium-binding bone-matrix protein that is primarily produced by mature osteoblasts and osteocytes. The secretion and carboxylation of osteocalcin are regulated by several molecular pathways, including:
1. Regulation by vitamin D:
Vitamin D is a key regulator of osteocalcin secretion and carboxylation. Vitamin D deficiency is associated with reduced osteocalcin levels, while vitamin D supplementation can increase osteocalcin production. This is thought to be due to the fact that vitamin D promotes the differentiation of osteoblasts, which leads to increased osteocalcin secretion.
2. Regulation by bone morphogenetic protein-2 (BMP-2):
BMP-2 is a growth factor that is essential for bone formation and remodeling. Studies have shown that BMP-2 stimulates osteocalcin secretion and carboxylation by promoting the differentiation of osteoblasts and increasing their expression of osteocalcin.
3. Regulation by insulin:
Insulin is another molecule that can regulate osteocalcin secretion and carboxylation. Insulin has been shown to stimulate osteoblast proliferation and differentiation, leading to increased osteocalcin production. Additionally, insulin promotes the carboxylation of osteocalcin, which is thought to enhance its activity in promoting bone mineralization.
4. Regulation by G-protein-coupled receptors:
Recent studies have identified G-protein-coupled receptors (GPCRs) as important regulators of osteocalcin secretion and carboxylation. GPCRs, such as GPRC6A and Mas-related G protein-coupled receptors, are expressed in osteoblasts and are thought to play a role in regulating osteocalcin production in response to various hormonal signals.
In summary, the secretion and carboxylation of osteocalcin are regulated by a variety of molecular pathways, including vitamin D, BMP-2, insulin, and G-protein-coupled receptors. These pathways are critical for maintaining proper bone formation and remodeling, and dysregulation of these pathways can lead to various bone disorders, such as osteoporosis and osteomalacia.
Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins (BMPs) are a family of growth factors that play important roles in bone formation, remodeling, and repair. BMPs have also been implicated in the pathogenesis of vascular calcification, which is the abnormal deposition of calcium in the walls of blood vessels. The role of BMPs in vascular calcification is thought to be as follows:
VSMCs normally have a contractile phenotype and are responsible for maintaining vascular tone and blood pressure. However, in response to certain stimuli, such as inflammation and oxidative stress, VSMCs can undergo a phenotypic switch from a contractile to an osteogenic phenotype. Under these conditions, VSMCs express osteoblast-like markers, such as alkaline phosphatase and osteocalcin, and deposit calcium in the extracellular matrix. BMPs have been shown to induce this phenotypic switch in VSMCs, leading to the formation of calcified nodules.
2. BMPs inhibit osteoclastic resorption of calcified areas:
Normally, calcified areas in the vascular wall are cleared by osteoclasts, which are bone-resorbing cells. However, BMPs have been shown to inhibit osteoclastic activity in VSMCs, leading to the accumulation of calcified areas in the vascular wall. This can result in the development of atherosclerotic plaques, which are characterized by the accumulation of cholesterol and other lipids in the arterial wall.
3. BMPs promote endothelial dysfunction:
Endothelial cells are responsible for maintaining the integrity and function of the vascular wall. However, BMPs have been shown to promote endothelial dysfunction, which can lead to inflammation, oxidative stress, and vascular damage. This can further promote the formation of calcified nodules and atherosclerotic plaques.
In summary, BMPs play an important role in the pathogenesis of vascular calcification by promoting osteogenic differentiation of VSMCs, inhibiting osteoclastic resorption of calcified areas, and promoting endothelial dysfunction. Targeting these pathways may provide new therapeutic strategies for the prevention and treatment of vascular calcification and atherosclerosis.
1.FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on kidney, heart, and parathyroid glands.
On a physiological level, FGF-23-klotho reduces the production and secretion of parathyroid hormone and reduces the production of vitamin D .
with hypocalcemia and secondary hyperparathyroidism.
also it has phosphoturiceffect so delay the hyperphosphatemia in CKD .
In the heart, FGF-23 can
increase risk of left ventricular hypertrophy
increase the risk of vascular calcification and vascular damage, which can worsen the effects of CKD.
2-Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system
sclerostin is a Wnt inhibitor secreted from osteoclast cells .
It has suppressive effects on bone morphogenic proteins.
interfere with systems for biological signalling that operate in the vessel wall and has been found to be upregulated in calcified aortic valves of patient.
Disturbed Wnt signalling could be particularly relevant in adynamic bone disease that is characterised by low bone turnover. In addition, increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with atherosclerosis, as Wnt signalling has a crucial role in human atherosclerosis.
3-Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts.
Osteocalcin is involved in the regulation of bone mineralisation,
a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form.The secretion of osteocalcin is regulated by PTH.
PTH stimulates the production of osteocalcin by binding to the receptor PTH1R and activation in the cAMP-dependent protein-kinase-A intracellular signalling pathway.
The carboxylation of osteocalcin is regulated by vitamin K, which is necessary for the conversion of undercarboxylated osteocalcin to its carboxylated form.
Vitamin K is required for the γ-carboxylation of glutamate residues in the N-terminal domain of osteocalcin. Vitamin K deficiency or chronic kidney disease can result in an increase in the proportion of uncarboxylated osteocalcin, resulting in decreased insulin sensitivity and increased cardiovascular risk.
4- Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 stimulates the osteo-regulatory gene MSX2 and enhances phosphate uptake .
BMP2 expression is increased in arterial calcification
BMP7 over expression suppresses vascular calcification in experimental animal models.
BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
in renal disease BMP7 expression is significantly reduced in renal tissue and circulatory BMP7 concentrations are low.
1. FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands. FGF 23 increase in chronic kidney disease lead to reduce po4 tubular reabsorption lead to early decrease in serum phosphate or delay it is retention. Effective FGF 23 on the kidney. It also affects parathyroid gland through FGF receptor 1 which lead to inhibition of parathyroid Hermon and also decrease activation of 1,25, hydroxyl vitamin D In CKD maladaptive effect on kidney in form of decrease FGF 23 degradation Fibroblast growth factor 23 (FGF23) is a hormone produced by bone cells that plays an important role in regulating phosphate and vitamin D metabolism. While FGF23 has adaptive effects in the normal kidney, high levels of FGF23 can have maladaptive effects on the kidney. Adaptive Effects: normal kidney, FGF23 maintain phosphate homeostasis by increasing renal excretion of phosphate and decreasing renal production of vitamin D. This lead to prevent hyperphosphatemia, Maladaptive Effects: in CKD increase osteocyte production of FGF23 can have maladaptive effects on the kidney. In CKD patients, decrease phosphate secretion, which leads to increased levels of FGF23 high levels of FGF23 promote the development of secondary hyperparathyroidism. Additionally, FGF23 has been shown to contribute to the development and progression of CKD by promoting fibrosis and inflammation in the kidney. maladaptive response in chronic kidney disease associated with increase mortality in all ckd stages including post renal transplantation as it there is high level of FGF23 in early months’ post transplantation. Effect of FGF 23 on the cardiovascular system. Left ventricular hypertrophy, high FGF 23 level independent of alfa klatho effect increase concentric left ventricular hypertrophy, may also there is association with FGF 23 and increase vascular wall calcification and arteriosclerosis but other studies mentioned that FGF 23 had ant calcification effect . Treatment with oral phosphate binders lead to decrease FGf 23 level and improvement in vascular flow mediated vasodilators. Effect of FGF 23 On parathyroid gland Fibroblast growth factor 23 (FGF23) also has both adaptive and maladaptive effects on the parathyroid glands. Adaptive Effects: In the normal parathyroid gland, FGF23 plays a role in regulating parathyroid hormone (PTH) secretion. Specifically, FGF23 decreases PTH secretion by directly inhibiting parathyroid gland function. This helps to maintain calcium and phosphate homeostasis in the body. Maladaptive Effects: However, in patients with chronic kidney disease (CKD), high levels of FGF23 can have maladaptive effects on the parathyroid glands. In CKD patients, the kidneys are less able to excrete phosphate, which leads to increased levels of FGF23. Over time, high levels of FGF23 can lead to a decrease in parathyroid gland function, with low activation of active vitamin D resulting in hypocalcemia and parathyroid stimulation to increase PTH secretion and secondary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in PTH secretion, which can lead to bone disease, cardiovascular disease, and other complications. Furthermore, excessive FGF23 levels have also been shown to cause pathological calcification of the parathyroid gland, leading to a decline in parathyroid gland function. In summary, while FGF23 plays an important role in regulating PTH secretion in the normal parathyroid gland, high levels of FGF23 can have maladaptive effects on the parathyroid gland in patients with chronic kidney disease, leading to the development of secondary hyperparathyroidism and other complications.
2. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system. Sclerostin is a soluble Wnt-inhibitor produced by osteocytes. Its presumed effects on bone and the cardiovascular system aRE: Bone: Sclerostin play a role in regulating bone remodeling through inhibiting the Wnt pathway, increase B catenin degradation and inhibit it s introduce to the nucleus then prevent transcription of target gene for osteoblast activity and its rule in bone formation. By inhibiting Wnt signaling, sclerostin suppresses osteoblast activity and bone formation, As a result, sclerostin is considered a negative regulator of bone mass and bone strength. Cardiovascular system: sclerostin may have a role in regulating vascular calcification and cardiovascular health. Also sclerostin associated with an increased risk of cardiovascular events and mortality in CKD and postmenopausal women. Additionally, sclerostin inhibition ( romosozumab ) can reduce vascular calcification and improve cardiovascular function. Overall, sclerostin is presumed to have a negative effect on bone by inhibiting bone formation and promoting bone resorption. Its effects on the cardiovascular system are still being studied,
Sclerostin inhibition has several therapeutic benefits, 1. Increased bone mass: sclerostin inhibition could increase bone formation and bone density, and reduce the risk of fractures. 2. Improved bone quality: Sclerostin inhibition changes in bone microarchitecture, and improvements in bone quality and strength. 3. Treatment of osteoporosis: Sclerostin inhibition studied as a treatment for osteoporosis, 4. Accelerated fracture healing: Sclerostin inhibition accelerate fracture healing in animal models, 5. For other bone disorders: Sclerostin inhibition is also studied in osteogenesis imperfecta and bone metastases. 6. Potential cardiovascular benefits: sclerostin inhibition may have cardiovascular benefits though reducing calcification and improving cardiovascular function. sclerostin inhibitors a new area of research, and more studies are needed to fully understand its therapeutic potential and safety profile..
1. Fgf23 is increased mainly from osteocyte early on in CKD due to hyperphosphatemia. It tries to compensate it through exercising a phosphaturic effect, decreasing the reabsorption of phosphat in renal tubule.
It is hypothesized early that this is his main adaptive function.
Later on, it is suggested that this may also be maladaptive due to increased Fgf23 even in the presence of relative hypophosphatemia. Some experts thinks that the downregulation of alpha klotho cofactor contribute to further increasing in fgf23 in Order to maintain its function on kidney.
Other experts suggest that there in decreased catabolism of fgf23 in CKD patients leading to high level of uncatabolised Fgf23.
It is suggested that there is osteocytes- overexpression of fgf23 on their surface due to maladaptive dysfunction of DMP1 (an inhibitor of fgf23).
Effects of fgf23 is divided to kotho dependent and klotho – independent:
Klotho dependent effects are inhibition of phosphat reabsorption from kidney what cause phosphaturic effect and inhibition of PTH secretion and it inhibit the production of 1,25 OH vitamin D.
Alpha kotho independent mechanism of fgf23 is left ventricular hypertrophy.
It is important to mention that epidemiological data about direct relationship between Fgf23 and arterial calcification are conflicting. Other study showed that reduction of fgf23 with phosphate binders lead to improvement in endothelial dysfunction (measurements of flow mediated vasodilation).
2.Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Wnt inhibitor sklerostin is considered as a high selective Wnt pathway inhibitor ( in contrast to DKK1 which considered as a panwnt inhibitor).
Wnt pathway activation lead to increased activation and differentiation of osteoblasts and bone gain. So , sclerostin through inhibition of wnt pathway, it will lead to decreased activation of osteoblasts and the balance of bone will shift toward osteoclasts.
Increased sclerostin lead to increased bone resorption and decreased mineralization.
The increased sclerostin level may be due to overproduction or decreased catabolism. It sill unclear.
The relationship between sclerostin and bone turnover is inversed.
It is important to mention that sclerostin overexpression lead to increased bone resistance to PTH.
On vascular system there is evidence of increased overexpression of sclerostin in calcified arteries and valves in relation to non calcified.
3.Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
The regulators of osteocalcin are : PTH and vitamin D. Both increase the level of osteocalcin secretion from osteoblasts through acting on PTHreceptors and activation of cAMP signaling pathway and vitamin D promoters site in BGLAP gene respectively.
The main factor for carboxylation of osteocalcin is vitamin K. The carboxylized form is the active form.
It is thought that the percentage of carboxylized to non carboxylized form of osteocalcin is 50%.
In context of vitamin K deficency and CKD ,high PTH and uremic toxin and deranged concentration of PTH there is an increased level of uncarboxylized osteocalcin. Uncarboxylized osteocalcin has negative effects on glucose metabolism leading to high insulin resistance and state of insulin deficiency, promoting cardiovascular calcification.
4.Discuss the role of bone morphogenic proteins in vascular calcification.
It is suggested that there is a dysregulation between BMP2 andBMP7, mostly studied in CKD-MBD. This dysbalance can lead to vascular calcification.
BMP2 is a inductor of smooth muscle calcification and is overexpressed in calcified vessel it upregulate natrium phosphate cotronsporter in smooth muscle cells leading to increased calcification.
On the other hand, BMP7 has inhibitory effect on vascular smooth muscle and are in CKD patient underexpressed.
1- FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands. the most prominent, bone-derived factor that is clearly abnormally elevated in CKD IS FGF23 The osteocyte is main production site in bone (Although the kidney, the liver, and coronary arteries have been suggested as sources of this factor) α-klotho a cofactor, is needed for FGF23 to bind to receptors The physiological role of FGF23 is to maintain balance of phosphorus and vitamin D
In CKD with loss of nephron
Decreases phosphorus reabsorption and excretion leading to hyperphosphatemia
FGF23 maintain balance and has adaptive phosphaturic effect And keep plasma concentrations of phosphate close to normal Other physiological actions of FGF23 are to reduce production and secretion of parathyroid hormone, and interference with metabolism of vitamin D, leading to a fall in the concentration of 1,25-dihydroxycholecalciferol
The maladaptive increase of FGF23 due to many suggestions # CKD inhibits FGF23 catabolism. # a relative resistance to its renal effects, possibly due to downregulation of tissue α-klotho, a cofactor for FGF23 signaling The maladaptive) increases in FGF23 concentrations are directly involved in the dismal clinical outcome in CKD. Findings from observational studies showed increased mortality with elevated concentrations of FGF23 in all stages of CKD, including after transplantation association of cardiovascular diseases and FGF23 in addition the prevalence of LVH IS strongly associated with increase FGF23 concentration FGF23-independent effects: Antioxidant Vasoprotective Anticalcifying Phosphaturia α-klotho-independent effect: Left ventricular hypertrophy 1. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system. Wnt inhibitors are secreted factors that interact with Wnt receptors or Wnt ligands and attenuate Wnt signalling activity (( Wnt signalling pathways play a key part in many diverse biological processes, such as cell proliferation, growth, migration, and differentiation)) Wnt signalling (including soluble inhibitors) has a key role in bone physiology and regulation of bone cellular activities and mineralisation processes. For example of Wnt inhibitors sclerostin and Dickkopf (Dkk1) both protein are soluble Wnt inhibitor the effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system bone dysregulation and induction adynamic bone disease inhibit osteoblast activity and decrease bon formation in addition the impact of calcified aortic valve # Sclerostin expression has also been shown in calcifying vascular smooth-muscle cells in vitro. And detectable in calciphylaxis cases Occurrence of sclerostin in calcified tissue is also 2. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation. It is regulated by the two major mineral and bone-controlling hormones vitamin D and parathyroid hormone Osteocalcin expression by the BGLAP gene and production are directly stimulated by vitamin D through a vitamin-D-responsive element located in the promoter region of BGLAP. Parathyroid hormone also stimulates osteocalcin production through its binding to the receptor PTH1R and activation of the cAMP-dependent proteinkinase-A intracellular signalling pathway There are two forms of osteocalcine 1-carboxylated form ( active form ) γ-carboxylated form acts as a regulator of bone mineralisation, affecting hydroxyapatite size and shape, and is a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form 2-uncarboxylated form Uncarboxylated (or undercarboxylated) forms of osteocalcin that are not bound to hydroxyapatite are released into the bloodstream, where they accumulate with fragments derived from direct proteolysis of osteocalcin after bone resorption, to constitute circulating osteocalcin # account for up to 50% of total osteocalcin in serum samples from normal people # its concentration affected by vit. K Status and degree of bonr remodling in CKD or in ESRD on dialysis Osteocalcin in chronic kidney disease Under conditions of normal kidney function and the absence of vitamin K deficiency, the proportion of uncarboxylated osteocalcin is low, stimulating insulin secretion and improving insulin sensitivity and energy handling. In the setting of chronic kidney disease or vitamin K deficiency, the amount of uncarboxylated osteocalcin increases, and as such negatively affects insulin secretion and sensitivity, promoting cardiovascular disease. Chronic kidney disease has a direct calcifying effect, not mediated by bone, and additionally vitamin K deficiency can also negatively affect the carboxylation status of matrix gla protein 3. Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins have a role in several clinical disorders ranging from vascular calcification (Rennenberg RJ, Schurgers LJ, Kroon AA, Stehouwer CD. Arterial calcifications. J Cell Mol Med 2010; 14: 2203–10 ) to obesity, diabetes, and cancer. ( Kim M, Choe S. BMPs and their clinical potentials. BMB Rep 2011; 44: 619–34) the bone morphogenetic proteins considered additional factors related to bon derived factors involved in vascular calcification need more study and researches support this suggestion
1.FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on kidney, heart, and parathyroid glands. FGF-23-klotho is one of the most extensively studied pathways in CKD due to its wide-reaching effects on the kidney, heart, and parathyroid glands. On a physiological level, FGF-23-klotho reduces the production and secretion of parathyroid hormone and reduces the production of vitamin D which can lead to reduced calcium absorption in the kidneys and increased calcium levels in the blood. In the heart, FGF-23 can have both adaptive and maladaptive effects. Adaptive effects include reducing the risk of left ventricular hypertrophy, which is a condition that can lead to heart failure. Maladaptive effects include increasing the risk of arterial calcification and vascular damage, which can worsen the effects of CKD.
2. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system Sclerostin is a Wnt inhibitor because it is almost exclusively bone derived. It acts as an inhibitor of the Wnt-catenin pathway and also has suppressive effects on bone morphogenic proteins. Sclerostin can interfere with systems for biological signalling that operate in the vessel wall and has been found to be upregulated in calcified aortic valves of patients undergoing haemodialysis. Disturbed Wnt signalling could be particularly relevant in adynamic bone disease that is characterised by low bone turnover. In addition, increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with atherosclerosis, as Wnt signalling has a crucial role in human atherosclerosis. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Osteocalcin is involved in the regulation of bone mineralisation, affecting hydroxyapatite size and shape, and is a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form.
The secretion of osteocalcin is regulated by PTH. PTH stimulates the production of osteocalcin by binding to the receptor PTH1R and activation in the cAMP-dependent protein-kinase-A intracellular signalling pathway.
The carboxylation of osteocalcin is regulated by vitamin K, which is necessary for the conversion of undercarboxylated osteocalcin to its carboxylated form.
Vitamin K is required for the γ-carboxylation of glutamate residues in the N-terminal domain of osteocalcin. Vitamin K deficiency or chronic kidney disease can result in an increase in the proportion of uncarboxylated osteocalcin, resulting in decreased insulin sensitivity and increased cardiovascular risk.
Discuss the role of bone morphogenic proteins in vascular calcification. Bone morphogenetic proteins (BMPs) are a family of proteins that are involved in a variety of biological functions, including the regulation of bone formation, cell differentiation, and vascular calcification. BMP2 and BMP7 have both been extensively studied in relation to experimental vascular calcification. BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake through upregulation of the type III sodium-dependent phosphate co-transporter in vascular smooth-muscle calcification. BMP2 expression is increased in arterial calcification, and BMP7 overexpression suppresses vascular calcification in experimental animal models. BMP2 and BMP7 may have a role in vascular calcification, either directly or through the modulation of other factors in the calcification process. BMPs play an important role in the regulation of vascular calcification, and an imbalance in their levels can result in an increased risk of vascular calcification in chronic kidney disease.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on the kidney, heart, and parathyroid glands.
FGF23 escapes physiological control in CKD, according to many studies. Phosphorus balance may regulate FGF23 in physiology. However, elevated FGF23 concentrations and mild hypophosphatemia in early-stage CKD imply a maladaptive rise owing to an undiscovered CKD cause.
Oral phosphate-binding treatment has inconsistent effects on FGF23 concentrations, even when phosphorus intake or plasma concentrations are lowered, supporting maladaptive FGF23 increases.
Despite significant hypophosphatemia in many patients, FGF23 concentrations decline for many months following kidney transplantation, suggesting that CKD itself promotes FGF23. 23 FGF23 is favorably related to phosphate concentration again after transplantation, indicating the maladaptive rise disappears with time. In peritoneal dialysis patients, practically all circulating FGF23 was intact, unlike in healthy persons. CKD inhibits FGF23 catabolism.
Wnt inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on the bone and the cardiovascular system.
Sclerostin also inhibits bone-morphogenic proteins.
Sclerostosis, Van Buchem’s disease, and genetically engineered mouse models demonstrate Wnt signaling’s clinical importance for bone. Overexpression of both sclerostin and DKK1 decreases bone mass and strength in animal models. In animal studies, sclerostin affects bones through local Wnt pathways and parathyroid hormone. These findings demonstrate the need for balanced Wnt signaling for bone health. Due to elevated sclerostin levels, CKD may disrupt this action. However, these increased concentrations have mixed effects: Reduced osteocytic Wnt-β-catenin signaling was an early finding in experimental CKD-MBD, but monocytes from CKD patients have increased Wnt-catenin pathway activity. Circulating Wnt inhibitors impact vascular calcification due to vascular smooth-muscle cell death. The current study shows that calcified aortic valves of hemodialysis patients upregulated sclerostin mRNA more than non-calcified controls. Calcifying vascular smooth-muscle cells in vitro causes them to express sclerostin.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Through its vitamin-K-dependent carboxylated form, osteocalcin regulates bone mineralization and hydroxyapatite size and shape.
Uncarboxylated (or under-carboxylated) osteocalcin that is not bonded to hydroxyapatite is discharged into the circulation and accumulates with fragments from direct proteolysis during bone resorption to create circulating osteocalcin.
Uncarboxylated osteocalcin is predicted to contribute up to 50% of total osteocalcin in blood samples from normal adults, notwithstanding the variability of circulating osteocalcin fragments.
In patients with CKD and those on hemodialysis, total osteocalcin concentrations are positively correlated with histological parameters of bone remodeling and affected by vitamin K status.
Lee and colleagues proposed that circulating uncarboxylated osteocalcin acts as a hormone to improve insulin secretion and sensitivity and prevent animal obesity. Several epidemiological studies have indicated a negative relationship between total blood osteocalcin concentrations and glycemia, glucose metabolism, and obesity. However, few of these investigations have examined uncarboxylated forms of osteocalcin, and they have not found similar relationships with glucose or adiposity, unlike evidence from murine models.
This variation may be due to osteocalcin genetics (one gene in humans, three genes in mice), concentrations, and metabolism.
Another possibility is the complicated relationship between vitamin K and osteocalcin. Vitamin K supplementation decreases the uncarboxylated forms of osteocalcin, but the few human studies that have been done show that it has different effects on glucose metabolism. There are also no solid data about how the oral vitamin K antagonist warfarin affects energy metabolism.
Discuss the role of bone morphogenic proteins in vascular calcification.
Although not synthesized in bone, several bone morphogenetic proteins may be connected to the CKD-MBD disease due to their biochemical features. Experimental vascular calcification has focused on BMP2 and BMP7.
BMP2 increases phosphate absorption by upregulating the type III sodium-dependent phosphate co-transporter in vascular smooth-muscle calcification and the osteo-regulatory gene MSX2. Inflammation increases vessel wall BMP2 expression, which inhibits calcification through MGP and SMAD6.
BMP2 induces calcification, and CKD patients had higher BMP2 serum concentrations and higher vascular stiffness. Intriguingly, BMP2 is associated with decreased expression of smooth-muscle cell markers in vascular smooth-muscle calcification, which promotes the osteoblastic-like phenotype, while BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
In renal disease models, BMP7 expression is significantly reduced in renal tissue, and circulatory BMP7 concentrations are low. BMP7 also prevents vascular calcification in experimental atherosclerosis, CKD, metabolic syndrome, and adynamic bone lesions.
BMP2 and BMP7 may protect podocytes from profibrotic stimuli and metabolically interact with SOST and DKK1 in bone.
BMP2 and BMP7’s relationship with calciprotein particles and arterial stiffness in CKD patients suggests systemic implications beyond these local cytokine-like effects.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.Decrease phosphate( by decreasing po42- tubular reabsorption) , decrease PTH( parathyroid gland) and decrease active vitamin D
Heart – lvh and cardiovascular calcification ( smooth muscle change into osteoblast)
CKD despite increasing FGF23 2nd hyperparathyroid develops
2 Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Bone- associated with adynamic bone disease/low turnover disease however it can be associated with vascular calcification
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
regulators- vitamin d and pth. Osteocalcin expression by the BGLAP gene and
production are directly stimulated by vitamin D through a
vitamin-D-responsive element located in the promoter
region of BGLAP. Parathyroid hormone also stimulates
osteocalcin production through its binding to the receptor
PTH1R and activation of the cAMP-dependent proteinkinase-A intracellular signalling pathway
2.Carboylated form of osteoclacin:
Uncarboylateed form
increased insulin resistance/secretion- atherosclerosis and soft tissue calcification
Vitamin D Deficiency and LVH
Discuss the role of bone morphogenic proteins in vascular calcification. ( they are cytokines that work via the intracelluar messaging pathway and have scope for differentiation.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.A. FGF23-klotko adaptive response:
B. FGF23-klotho maladaptive response:
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
1.Bone:
2.Cardiovascular system:
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.Discuss the role of bone morphogenic proteins in vascular calcification.
2.Carboylated form of osteoclacin:
3.Uncarboylated form”
Discuss the role of bone morphogenic proteins in vascular calcification.
1- FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands. A. FGF23-klotko adaptive response:
B. FGF23-klotho maladaptive response:
2- Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system. Wnt/ B-catenin is intracellular pathway which regulate osteoblastic activity, when wnt is activated, bone is formed, and inhibited, the bone formation is inhibited.
Sclerostin is a soluble inhibitor of wnt.
Sclerostin is increased in CKD patients, but unknown due to increase secretion or due to decreased clearance.
Increased sclerostin in ckd decreases bone formation, precipitating adynamic bone disease.
high sclerostin levels with seemingly increased vascular calcification rate and severity, as wnt regulates apoptosis of vascular smooth muscles cells.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.1.Osteocalcin is stimulated by
2.Carboylated form of osteoclacin:
3.Uncarboylated form”
Discuss the role of bone morphogenic proteins in vascular calcification.
FGF-23 and Klotho have separate and related effects on bone. FGF-23 starts to increase in the early stages of CKD, most probably to compensate for the decrease in phosphate excretion. Klotho and FGF23 have a lowering effect on PTH as well. In the early stages, elevation of FGF23 coincides with low phosphate which may reflect maladaptation.
Sclerostin, which is an important Wnt inhibitor. Wnt signaling is an important pathway important for bone mineralization. Sclerostin is a target of treatment (by use of Rmosuzumab). WNT signaling also has an important role in human atherosclerosis.
Osteocalcin is controlled by both vitamin D and PTH. The uncarboxylated form is the one that constitutes the circulating portion of osteocalcin. The uncarboxylated form increased insulin sensitivity and prevented adiposity in mice.
Bone morphogenic proteins like osteogenin, BMP2, and BMP7. Especially BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake through upreulation of type 3 sodium-dependent phosphate cotransporter in vascular smooth muscle calcification. BMP2 is considered an important induction factor for calcification
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.The physiological role of FGF23 is to maintain balance of phosphorus and vitamin D; its concentration increases as the glomerular filtration rate falls, because the kidney has a key role in excreting excess phosphate.Other physiological actions of FGF23 are to reduce production and secretion of parathyroid hormone, and interference with metabolism of vitamin D, leading to a fall in the concentration of 1,25-dihydroxycholecalciferol (the active form of vitamin D).
Direct FGF23 toxicity would be directed toward the cardiovascular system (left ventricular hypertrophy & calcification of the arterial wall).
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.sclerostin showed strong negative associations with parameters of bone turnover, pointing towards a role of high sclerostin concentrations in induction of adynamic bone disease, or vice versa.
Wnt signalling has a crucial role in human atherosclerosis, and therefore increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with this process. In view of the crucial role of apoptosis of vascular smooth-muscle cells in vascular calcification, circulating Wnt inhibitors also affect this process.
Sclerostin expression has also been shown in calcifying vascular smooth muscle cells& in patients with calciphylaxis.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.It is regulated by the two major mineral and bone-controlling hormones, vitamin D and parathyroid hormone. Osteocalcin expression by the BGLAP gene and production are directly stimulated by vitamin D through a vitamin-D-responsive element located in the promoter region of BGLAP. Parathyroid hormone also stimulates osteocalcin production through its binding to the receptor PTH1R and activation of the cAMP-dependent protein- kinase-A intracellular signalling pathway.
Under conditions of normal kidney function and the absence of vitamin K de ciency, the proportion of uncarboxylated osteocalcin is low, stimulating insulin secretion and improving insulin sensitivity and energy handling. In the setting of chronic kidney disease or vitamin K de ciency, the amount of uncarboxylated osteocalcin increases, and as such negatively affects insulin secretion and sensitivity, promoting cardiovascular disease.
Discuss the role of bone morphogenic proteins in vascular calcification.CKD could be a disorder of BMP2 and BMP7 dysregulation, potentially involved in the pathological processes of calci cation in orthotopic and ectopic tissues.
BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake through upregulation of the type III sodium- dependentphosphateco-transporter in vascular smooth- muscle calcification.
BMP2 expression is increased in the vessel wall in response to inflammation,and these calcifying effects are inhibited by MGP (which binds to BMP2) and SMAD6.
BMP2 is thus regarded as an important induction factor of calcification. Clinically, serum concentrations of BMP2 are increased in patients with CKD and are positively associated with vascular sitffness.
BMP7 represents an inhibitor of calcification possibly implicated in bone and vascular disease. In different experimental models of renal disease, a signi cant reduction of BMP7 expression occurs in renal tissue, and circulating BMP7 concentrations are reported to be low.
Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins have a role in several clinical disorders ranging from vascular calcification to obesity, diabetes, and cancer.
Bone morphogenetic proteins can be generally regarded as local (auto or paracrine) modulators of the inflamma- tory effects of transforming growth factor β.
some bone morphogenetic proteins seem to be linked with the CKD-MBD syndrome.
In particular, BMP2 and BMP7 have both been extensively studied in relation to experimental vascular calcification.
BMP2 expression is increased in the vessel wall in response to inflammation,and these calcifying effects are inhibited by MGP (which binds to BMP2) and SMAD6.
BMP2 is thus regarded as an important induction factor of calcification.
Clinically, serum concentrations of BMP2 are increased in patients with CKD and are positively associated with vascular stiffness.
BMP7 promotes the phenotype of vascular smooth-muscle calcification, and thus represents an inhibitor of calcification possibly implicated in bone and vascular disease.
BMP2 and BMP7 have been suggested to have anabolic effects through interaction with SOST and DKK1 in bone and to protect podocytes from profibrotic stimuli.Besides these local cytokine- like effects, BMP2 and BMP7 might have systemic effects in view of their reported association with calciprotein particles and arterial stiffness in patients with CKD.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands?
1- adaptive response:
2- maladaptive response:
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
1.Bone:
2.Cardiovascular system:
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
1.Osteocalcin is stimulated by
2.Carboylated form of osteoclacin:
3.Uncarboylated form”
IV.Discuss the role of bone morphogenic proteins in vascular calcification.
1.BMP2
2.BMP7:
by promoting vascular smooth muscle cell phenotype
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin, also known as bone gla protein, is a 6 kD calcium-binding bone-matrix protein produced by osteoblasts, and is one of the most abundant non-collagen proteins in bone. It is regulated by the two major mineral and bone-controlling hormones, vitamin D and parathyroid hormone.
No receptor for osteocalcin has been identified, but the protein might modulate activities of the G-coupled protein receptor GPRC6A, which is widely expressed.Osteocalcin acts as a regulator of bone mineralisation, affecting hydroxyapatite size and shape, and is a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form.
Uncarboxylated (or under- carboxylated) forms of osteocalcin that are not bound to hydroxyapatite are released into the bloodstream, where they accumulate with fragments derived from direct proteolysis of osteocalcin after bone resorption, to constitute circulating osteocalcin.
Concentrations of circulating uncarboxylated forms of osteocalcin are affected by vitamin K status and directly by the degree of bone remodelling, as reported in both patients with CKD and those undergoing haemodialysis, for whom circulating concentration of total osteocalcin is positively correlated with histological parameters of bone remodelling.
There’s an inverse link between total osteocalcin concentrations in serum samples and glycaemia, glucose metabolism, and measures of adiposity.
The complex association between vitamin K status and osteocalcin could be another explanation. Vitamin K supplementation decreases concentrations of uncarboxylated forms of osteocalcin,but has shown variable effects on glucose metabolism in the small number of human studies reported,and no solid data about the effect the of oral vitamin K antagonist, warfarin, on energy metabolism are available.
Schafer and colleagues reported that parathyroid hormone increased and alendronate reduced concentrations of uncarboxylated osteocalcin, and that these changes were associated with changes in bodyweight, fat mass, and serum concentrations of adiponectin, but the investigators did not find linkage between changes in uncarboxylated osteocalcin and changes in concentrations of glucose and insulin.
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Wnt signalling is of great importance for skeletal health. Besides being an inhibitor of the Wnt-catenin pathway ,sclerostin acts by other modes—eg, suppressive effects on bone morphogenic proteins.The clinical relevance of Wnt signalling for bone can easily be established in human disorders such as sclerostosis and Van Buchem’s disease, and in genetically modified rodent models.Although reduced activity of sclerostin and DKK1 leads to increased bone mass and strength, the opposite occurs in animal models with overexpression of both sclerostin and Dkk1.In addition to direct effects of sclerostin on local Wnt pathways, the effects of parathyroid hormone on bone also depend on sclerostin activity. All these data point to the importance of balanced activity of Wnt signalling for bone health. In CKD, this activity is probably disturbed because of typically increased circulating concentrations of sclerostin.However, the effects of these increased concentrations are not straightforward; on the one hand, reduced osteocytic Wnt-β-catenin signalling was an early finding during the course of experimental CKD-MBD,but on the other, activity of Wnt-catenin pathways is increased in monocytes from patients with CKD.
Besides affecting bone metabolism, Wnt signalling has a crucial role in human atherosclerosis,and therefore increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with this process.
Additionally, findings from experimental studies have shown a wide range of effects of Wnt activation on cell function for vascular smooth muscle, including protection against apoptosis.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
The physiological role of FGF23 is to maintain balance of phosphorus and vitamin D; its concentration increases as the glomerular filtration rate falls, because the kidney has a key role in excreting excess phosphate. Reduced ultrafiltration and excretion of phosphate due to a decreased glomerular filtration rate is balanced by decreased tubular reabsorption of phosphate due to the action of FGF23, which is an important physiological homoeostatic mechanism, tending to keep plasma concentrations of phosphate close to normal. Other physiological actions of FGF23 are to reduce production and secretion of parathyroid hormone, and interference with metabolism of vitamin D, leading to a fall in the concentration of 1,25-dihydroxycholecalciferol (the active form of vitamin D).Possibly related to the effect of FGF23 on activation of vitamin D are intriguing clinical and experimental findings that point to an important role of calcium as an inducer of FGF23 secretion.This suggested role of calcium possibly explains the lack of FGF23-lowering potency of therapy with calcium-based phosphatebinder. early-stage CKD, however, increased concentrations of FGF23 coincide with slight hypophosphataemia, suggesting that this increase is maladaptive, due to an unidentified CKD- related factor.Another argument for maladaptive increments of FGF23 comes from the non-consistent effects of oral phosphate-binding therapy on FGF23 concentrations, even when phosphorus uptake or plasma concentrations are adequately reduced.An additional reason to assume that CKD itself, separate from phosphate balance or concentrations, induces FGF23 is the finding that after kidney transplantation, FGF23 concentrations fall for several months, despite pronounced hypo- phosphataemia in many patients.At longer post- transplantation follow-up, FGF23 is positively associated with phosphate concentration again, suggesting disappearance of the maladaptive increase with time.In further investigations of the effects of CKD (and not phosphate concentrations) on FGF23, almost all circulating FGF23 was intact in patients undergoing peritoneal dialysis,by contrast with healthy people.This finding suggests that CKD inhibits FGF23 catabolism.
However, besides being maladaptive (especially in early stages of CKD), some evidence suggests that FGF23 concentrations rise because of a relative resistance to its renal effects, possibly due to downregulation of tissue α-klotho, a cofactor for FGF23 signalling.
Because the leading cause of morbidity and mortality in CKD is cardiovascular disease, the obvious site for direct FGF23 toxicity would be the cardiovascular system. Indeed, as for mortality, increased prevalence of left ventricular hypertrophy is strongly associated with increased FGF23 concentrations.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.First the adaptive mechanism of FGF23 Kolotho is taking place early in CKD which is newly discovered becuase of that there is no hyperphophatemia in early CKD stages because FGF23 is decrease reabsorbtion of phophate in the kidney but with advanced CKD the FGF 23 loss the adaptive mechanism and lead to hyperphophatemia with increase in PTH level and both of them will leads to LVH and incresae the cardiovascular calcification .
FGF23 is affecting multiple organs and can leads to increase the cytokines and inflanmatory response in the body .
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.As we all know that wint bathway is for bone formation and scelerostin is inhibit wibt bathway and inhibits bone formation . In case of osteoporosis the patient will have high sclerostin level with no bone formation and loss of balance between bone formation and bone resorption which leads to osteoporosis .
It has been known that sclerostin increased in CKD patient whether becuse of increased secretion or decrease excretion not clear.High sclerostin levels with seemingly increased vascular calcification rate and severity,as wnt regulates apoptosis of vascular sm.cells.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.osteocalcin is calcium binding bone matrix protein, produced by osteoblasts under control of vit D and PTH.
It is a regulator of bone mineralization
in CKD stage 3 to5 the level of. decraboxilated level to osteoclastin is high and this will affect the miniralization ,on the other hans as this osteocalstin is decarboxliated to active form under Vit K ,for that warfarin increase the uncarboxilated osteoclastin .
Discuss the role of bone morphogenic proteins in vascular calcification.
The BMPs are severla protiends which belongs to TGF B and they has a majour role in vascular calcifications speciaaly the BMP 2 AND BMP7 .
BMP2enhance Pi vesseles uptake while BMP7 IS a good type of protein which is decrease with advanced CKD and this protein had a good effect which is decrease the vascular calcification and has anti fibrotic effects
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on the kidney, heart, and parathyroid glands.
Wnt inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and the cardiovascular system.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Discuss the role of bone morphogenic proteins in vascular calcification.
1-FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
Adaptive effect on kideny and parathyroid gland in combination with koltho have increase po4 excretion and decrease pth secretion
Mal adaptive effect
In advanced kidney disease will loss of koltho so fgf23 loss phosphaturic effect
Increase pth
Lead to ventricular hypertrophy and accelerate atherosclerosis and vascular calcification.
2-Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
sclerostin inhibits the wnt signaling pathway, sclerostin decreases bone formation and increases bone resorption, resulting in a reduction in bone density and oesteoprosis
recent research indicates that sclerostin may contribute to the pathogenesis of cardiovascular disease. sclerostin has been detected in vascular tissue, and studies have shown that patients with cardiovascular disease have elevated sclerostin levels. this may be due to the wnt signaling pathway’s role in vascular calcification, which is believed to contribute to the development of atherosclerosis and other cardiovascular diseases. sclerostin may promote vascular calcification by inhibiting the wnt signaling pathway in vascular smooth muscle cells.
3-Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Main regulator for secretion of osteocalcin from oesteoblast are vit d and pth .
The carboxylated form vit k dependant so any affection on vit k reflected on its carboxylation and regulate bone mineralization changing the size and shape of the hydroxyapatite.Potential modulator of osteoblast/osteoclast activities
4-Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 and BMP7 have both been extensively studied in relation to experimental vascular calcification.
BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake.
The BMP2 expression is increased in arterial calcification, and BMP7 overexpression suppresses vascular calcification in experimental animal models.
BMP2 and BMP7 may have a role in vascular calcification, either directly or through the modulation of other factors in the calcification process.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
Kidney
adaptive
Fgf-23 decreases tubular phosphorus reabsorption, attenuate hyperphosphatemia due to decreased GFR.
2- Decrease PTH, Decrease vit D
Maladapative
In early stages of ckd, increased FGF-23 can cause hyphosphatemia
2- after kidney transplantation there is always hyperphosphatemia, but FGF-23 drop over several months
BONE
There is increase in expression of FGF-23 by osteocytes in early stages of CKD, due to disturbance between regulators.
Heart
FGF-23 is associated with increased CVS mortality and morbidity 2ry to left vent, hypertrophy and vascular calcification
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.Wnt/ B-catenin is intracellular pathway which regulate osteoblastic activity, when wnt is activated, bone is formed, and inhibited, the bone formation is inhibited.
Sclerostin is a soluble inhibitor of wnt.
Sclerostin is increased in CKD patients, but unknown due to increase secretion or due to decreased clearance.
Increased sclerostin in ckd decreases bone formation, precipitating adynamic bone disease.
high sclerostin levels with seemingly increased vascular calcification rate and severity,as wnt regulates apoptosis of vascular sm.cells
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.osteocalcin is calcium binding bone matrix protein, produced by osteoblasts under control of vit D and PTH. It has 2 forms carboxylated which is attached to hydroxyapatite and uncarboxylated form which circulates in the serum and account for 50% of total osteocalcin. the carboxylation is vit K dependent so it is affected by factors affecting vit k level and vit k antagoinists like warfarin
in ckd patient the uncarboxylate osteocalcin ratio is increased
unfractioned form in animal increase insulin sensitivity and secretion and protect from adiposity
Discuss the role of bone morphogenic proteins in vascular calcificationBMPs are member of the TGF-β superfamily and includes at least 30 proteins
They have a wide group of functions from vascular calcification to obesity.
BMP2 and BMP 7 are associated vascular calcification,
I.FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
A. FGF23-klotko adaptive response:
B. FGF23-klotho maladaptive response:
II.Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
1.Bone:
2.Cardiovascular system:
III. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
1.Regulators of osteocalcin; osteocalcin is stimulated by
2.Carboylated (Vitamin K dependent) form of osteoclacin:
3.Uncarboylated form e.g., CKD, vitamin K deficiency:
IV.Discuss the role of bone morphogenic proteins in vascular calcification.
1.Bone morphogenetic protein 2(BMP2)
2.Bone morphogenic protein 7(BMP7):
**Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
The mean regulator of osteocalcin are vitamin D through vitamin D responsive elements in the BGLAP gene and PTH through PTH1R, it secreted from osteoblast
The carboxylation affected by vitamin K status and by histological parameters of bone remodeling, it causes increase insulin secretion and sensitivity
Also increase in ckd, warfarin treatment increase uncarboxylated osteocalcin and decrease carboxylated osteocalcin
**Discuss the role of bone morphogenic proteins in vascular calcification.
Ranging from vascular calcification to obesity, diabetes and cancer, it can be regarded as cytokines with growth and differentiation properties, as local autocrine or paracrine modulators of inflammatory effects of TGF B,
BMP2 associated with vascular stiffness where as BMP7 an inhibitor of calcification
Both BMP2 and BMP7 has anabolic effects through interaction with SOSTand DKK1 in the bone and protect podocyte from profibrotic stimuli in addition to the local cytokines like effects.
**FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
It lead to increase phosphaturia, interfere with the metabolism of vitamin D lead to decrease calcitriol, it decrease the production and the secretion of PTH,
It effects on the heart lead to the left ventricular hypertrophy, vascular calcification and endothelial dysfunction
It also has antioxidants, vasoprotective, anticalcifying, phosphaturia
**Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system
It causes suppressive effects on bone morphogenic protein
It increase bone mass and strength
It has a role in atherosclerosis, causes vascular calcification, calcified aortic valve, it has an effect on calciphylaxis and also in Adynamic bone disease negative association of sclerostin on bone turnover, in addition to the negative effects on PTH
1. FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
The initial PO4 retention in CKD leads to increased secretion of FGF23, the latter is phosphaturic hormone (via inhibiting reabsorption of PO4 in PCT), but as CKD progresses FGF23 keep rising leading to inhibition of 1,and 25 hydroxylation if vitamin, and consequently increased secrion of PTH from parathyroid gland.
There is a link between elevated FGF-23 levels and multiple cardiovascular outcomes, including hypertension, left ventricular hypertrophy and cardiovascular events and mortality.
2. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Sclerostin inhibits the Wnt signaling pathway, which promotes bone development. By inhibiting this pathway, sclerostin decreases bone formation and increases bone resorption, resulting in a reduction in bone density. This is believed to contribute to the development of osteoporosis and other bone disorders.
Recent research indicates that sclerostin may contribute to the pathogenesis of cardiovascular disease. Sclerostin has been detected in vascular tissue, and studies have shown that patients with cardiovascular disease have elevated sclerostin levels. This may be due to the Wnt signaling pathway’s role in vascular calcification, which is believed to contribute to the development of atherosclerosis and other cardiovascular diseases. Sclerostin may promote vascular calcification by inhibiting the Wnt signaling pathway in vascular smooth muscle cells, as hypothesized.
3. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
*.vitamin D:
Vitamin D is an important osteocalcin secretion and carboxylation regulator. Vitamin D deficiency is associated with decreased osteocalcin levels, whereas supplementation with vitamin D can increase osteocalcin production. This is believed to be because vitamin D promotes the differentiation of osteoblasts, resulting in increased osteocalcin secretion.
* morphogenetic protein 2
BMP-2 is an essential growth factor for bone formation and remodeling. Studies have demonstrated that BMP-2 stimulates osteocalcin secretion and carboxylation by promoting osteoblast differentiation and increasing osteocalcin expression.
*insulin:
Insulin is another molecule capable of regulating the secretion and carboxylation of osteocalcin. It has been demonstrated that insulin stimulates osteoblast proliferation and differentiation, resulting in increased osteocalcin production. Additionally, insulin promotes the carboxylation of osteocalcin, which is believed to increase its bone mineralization-promoting activity.
4. Discuss the role of bone morphogenic proteins in vascular calcification.
BMP2 increases phosphate absorption through upregulation of the type III sodium-dependent phosphate co-transporter in vascular smooth-muscle calcification and the osteoregulatory gene MSX2. Inflammation increases vessel wall BMP2 expression, which inhibits calcification by way of MGP and SMAD6.
BMP2 induces calcification, and CKD patients had higher serum concentrations of BMP2 and stiffer blood vessels. BMP2 is associated with decreased expression of smooth-muscle cell markers in vascular smooth-muscle calcification, which promotes the osteoblastic-like phenotype. In contrast, BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
In renal disease models, BMP7 expression in renal tissue and BMP7 concentrations in the blood are significantly diminished. In experimental atherosclerosis, CKD, metabolic syndrome, and adynamic bone lesions, BMP7 also prevents vascular calcification.
BMP2 and BMP7 may protect podocytes from profibrotic stimuli and have metabolic interactions with SOST and DKK1 in bone.
BMP2 and BMP7’s association with calciprotein particles and arterial stiffness in CKD patients suggests systemic implications beyond these local cytokine-like effects.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Sclerostin is a soluble inhibitor of the Wnt signaling pathway that is expressed by osteocytes in bone. It plays a key role in the regulation of bone remodeling, and its levels are known to be altered in various bone and cardiovascular diseases. The effects of sclerostin on bone and cardiovascular disease are presumed to be as follows:
1. Effects on bone:
Sclerostin inhibits the Wnt signaling pathway, which is responsible for promoting bone formation. By inhibiting this pathway, sclerostin reduces bone formation and promotes bone resorption, leading to a decrease in bone density. This is thought to play a role in the pathogenesis of osteoporosis and other bone disorders. Anti-sclerostin antibodies have been developed as a potential treatment for osteoporosis, with initial studies showing promising results in increasing bone mineral density.
2. Effects on cardiovascular disease:
Recent studies have suggested that sclerostin may play a role in the pathogenesis of cardiovascular disease. Sclerostin has been shown to be present in vascular tissue, and studies have demonstrated that sclerostin levels are elevated in patients with cardiovascular disease. This may be due to the role of the Wnt signaling pathway in vascular calcification, which is thought to contribute to the development of atherosclerosis and other cardiovascular diseases. It has been suggested that sclerostin may promote vascular calcification by inhibiting the Wnt signaling pathway in vascular smooth muscle cells.
In summary, sclerostin, a Wnt inhibitor, plays a key role in bone remodeling and is involved in the pathogenesis of various bone disorders. Additionally, sclerostin has been implicated in the development of cardiovascular disease, with elevated levels associated with vascular calcification. Treatments targeting sclerostin inhibition are being developed as potential therapies for these conditions.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin is a calcium-binding bone-matrix protein that is primarily produced by mature osteoblasts and osteocytes. The secretion and carboxylation of osteocalcin are regulated by several molecular pathways, including:
1. Regulation by vitamin D:
Vitamin D is a key regulator of osteocalcin secretion and carboxylation. Vitamin D deficiency is associated with reduced osteocalcin levels, while vitamin D supplementation can increase osteocalcin production. This is thought to be due to the fact that vitamin D promotes the differentiation of osteoblasts, which leads to increased osteocalcin secretion.
2. Regulation by bone morphogenetic protein-2 (BMP-2):
BMP-2 is a growth factor that is essential for bone formation and remodeling. Studies have shown that BMP-2 stimulates osteocalcin secretion and carboxylation by promoting the differentiation of osteoblasts and increasing their expression of osteocalcin.
3. Regulation by insulin:
Insulin is another molecule that can regulate osteocalcin secretion and carboxylation. Insulin has been shown to stimulate osteoblast proliferation and differentiation, leading to increased osteocalcin production. Additionally, insulin promotes the carboxylation of osteocalcin, which is thought to enhance its activity in promoting bone mineralization.
4. Regulation by G-protein-coupled receptors:
Recent studies have identified G-protein-coupled receptors (GPCRs) as important regulators of osteocalcin secretion and carboxylation. GPCRs, such as GPRC6A and Mas-related G protein-coupled receptors, are expressed in osteoblasts and are thought to play a role in regulating osteocalcin production in response to various hormonal signals.
In summary, the secretion and carboxylation of osteocalcin are regulated by a variety of molecular pathways, including vitamin D, BMP-2, insulin, and G-protein-coupled receptors. These pathways are critical for maintaining proper bone formation and remodeling, and dysregulation of these pathways can lead to various bone disorders, such as osteoporosis and osteomalacia.
Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins (BMPs) are a family of growth factors that play important roles in bone formation, remodeling, and repair. BMPs have also been implicated in the pathogenesis of vascular calcification, which is the abnormal deposition of calcium in the walls of blood vessels. The role of BMPs in vascular calcification is thought to be as follows:
1. BMPs promote osteogenic differentiation of vascular smooth muscle cells (VSMCs):
VSMCs normally have a contractile phenotype and are responsible for maintaining vascular tone and blood pressure. However, in response to certain stimuli, such as inflammation and oxidative stress, VSMCs can undergo a phenotypic switch from a contractile to an osteogenic phenotype. Under these conditions, VSMCs express osteoblast-like markers, such as alkaline phosphatase and osteocalcin, and deposit calcium in the extracellular matrix. BMPs have been shown to induce this phenotypic switch in VSMCs, leading to the formation of calcified nodules.
2. BMPs inhibit osteoclastic resorption of calcified areas:
Normally, calcified areas in the vascular wall are cleared by osteoclasts, which are bone-resorbing cells. However, BMPs have been shown to inhibit osteoclastic activity in VSMCs, leading to the accumulation of calcified areas in the vascular wall. This can result in the development of atherosclerotic plaques, which are characterized by the accumulation of cholesterol and other lipids in the arterial wall.
3. BMPs promote endothelial dysfunction:
Endothelial cells are responsible for maintaining the integrity and function of the vascular wall. However, BMPs have been shown to promote endothelial dysfunction, which can lead to inflammation, oxidative stress, and vascular damage. This can further promote the formation of calcified nodules and atherosclerotic plaques.
In summary, BMPs play an important role in the pathogenesis of vascular calcification by promoting osteogenic differentiation of VSMCs, inhibiting osteoclastic resorption of calcified areas, and promoting endothelial dysfunction. Targeting these pathways may provide new therapeutic strategies for the prevention and treatment of vascular calcification and atherosclerosis.
1.FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on kidney, heart, and parathyroid glands.
On a physiological level, FGF-23-klotho reduces the production and secretion of parathyroid hormone and reduces the production of vitamin D .
with hypocalcemia and secondary hyperparathyroidism.
also it has phosphoturiceffect so delay the hyperphosphatemia in CKD .
In the heart, FGF-23 can
increase risk of left ventricular hypertrophy
increase the risk of vascular calcification and vascular damage, which can worsen the effects of CKD.
2-Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system
sclerostin is a Wnt inhibitor secreted from osteoclast cells .
It has suppressive effects on bone morphogenic proteins.
interfere with systems for biological signalling that operate in the vessel wall and has been found to be upregulated in calcified aortic valves of patient.
Disturbed Wnt signalling could be particularly relevant in adynamic bone disease that is characterised by low bone turnover. In addition, increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with atherosclerosis, as Wnt signalling has a crucial role in human atherosclerosis.
3-Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts.
Osteocalcin is involved in the regulation of bone mineralisation,
a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form.The secretion of osteocalcin is regulated by PTH.
PTH stimulates the production of osteocalcin by binding to the receptor PTH1R and activation in the cAMP-dependent protein-kinase-A intracellular signalling pathway.
The carboxylation of osteocalcin is regulated by vitamin K, which is necessary for the conversion of undercarboxylated osteocalcin to its carboxylated form.
Vitamin K is required for the γ-carboxylation of glutamate residues in the N-terminal domain of osteocalcin. Vitamin K deficiency or chronic kidney disease can result in an increase in the proportion of uncarboxylated osteocalcin, resulting in decreased insulin sensitivity and increased cardiovascular risk.
4- Discuss the role of bone morphogenic proteins in vascular calcification.
1. FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
FGF 23 increase in chronic kidney disease lead to reduce po4 tubular reabsorption lead to early decrease in serum phosphate or delay it is retention.
Effective FGF 23 on the kidney.
It also affects parathyroid gland through FGF receptor 1 which lead to inhibition of parathyroid Hermon and also decrease activation of 1,25, hydroxyl vitamin D In CKD maladaptive effect on kidney in form of decrease FGF 23 degradation Fibroblast growth factor 23 (FGF23) is a hormone produced by bone cells that plays an important role in regulating phosphate and vitamin D metabolism. While FGF23 has adaptive effects in the normal kidney, high levels of FGF23 can have maladaptive effects on the kidney.
Adaptive Effects:
normal kidney, FGF23 maintain phosphate homeostasis by increasing renal excretion of phosphate and decreasing renal production of vitamin D. This lead to prevent hyperphosphatemia,
Maladaptive Effects:
in CKD increase osteocyte production of FGF23 can have maladaptive effects on the kidney. In CKD patients, decrease phosphate secretion, which leads to increased levels of FGF23 high levels of FGF23 promote the development of secondary hyperparathyroidism. Additionally, FGF23 has been shown to contribute to the development and progression of CKD by promoting fibrosis and inflammation in the kidney. maladaptive response in chronic kidney disease associated with increase mortality in all ckd stages including post renal transplantation as it there is high level of FGF23 in early months’ post transplantation.
Effect of FGF 23 on the cardiovascular system.
Left ventricular hypertrophy, high FGF 23 level independent of alfa klatho effect increase concentric left ventricular hypertrophy, may also there is association with FGF 23 and increase vascular wall calcification and arteriosclerosis but other studies mentioned that FGF 23 had ant calcification effect . Treatment with oral phosphate binders lead to decrease FGf 23 level and improvement in vascular flow mediated vasodilators.
Effect of FGF 23 On parathyroid gland
Fibroblast growth factor 23 (FGF23) also has both adaptive and maladaptive effects on the parathyroid glands.
Adaptive Effects:
In the normal parathyroid gland, FGF23 plays a role in regulating parathyroid hormone (PTH) secretion. Specifically, FGF23 decreases PTH secretion by directly inhibiting parathyroid gland function. This helps to maintain calcium and phosphate homeostasis in the body.
Maladaptive Effects:
However, in patients with chronic kidney disease (CKD), high levels of FGF23 can have maladaptive effects on the parathyroid glands. In CKD patients, the kidneys are less able to excrete phosphate, which leads to increased levels of FGF23. Over time, high levels of FGF23 can lead to a decrease in parathyroid gland function, with low activation of active vitamin D resulting in hypocalcemia and parathyroid stimulation to increase PTH secretion and secondary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in PTH secretion, which can lead to bone disease, cardiovascular disease, and other complications.
Furthermore, excessive FGF23 levels have also been shown to cause pathological calcification of the parathyroid gland, leading to a decline in parathyroid gland function.
In summary, while FGF23 plays an important role in regulating PTH secretion in the normal parathyroid gland, high levels of FGF23 can have maladaptive effects on the parathyroid gland in patients with chronic kidney disease, leading to the development of secondary hyperparathyroidism and other complications.
2. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Sclerostin is a soluble Wnt-inhibitor produced by osteocytes. Its presumed effects on bone and the cardiovascular system aRE:
Bone: Sclerostin play a role in regulating bone remodeling through inhibiting the Wnt pathway, increase B catenin degradation and inhibit it s introduce to the nucleus then prevent transcription of target gene for osteoblast activity and its rule in bone formation. By inhibiting Wnt signaling, sclerostin suppresses osteoblast activity and bone formation, As a result, sclerostin is considered a negative regulator of bone mass and bone strength.
Cardiovascular system: sclerostin may have a role in regulating vascular calcification and cardiovascular health. Also sclerostin associated with an increased risk of cardiovascular events and mortality in CKD and postmenopausal women. Additionally, sclerostin inhibition ( romosozumab ) can reduce vascular calcification and improve cardiovascular function.
Overall, sclerostin is presumed to have a negative effect on bone by inhibiting bone formation and promoting bone resorption. Its effects on the cardiovascular system are still being studied,
Sclerostin inhibition has several therapeutic benefits,
1. Increased bone mass: sclerostin inhibition could increase bone formation and bone density, and reduce the risk of fractures.
2. Improved bone quality: Sclerostin inhibition changes in bone microarchitecture, and improvements in bone quality and strength.
3. Treatment of osteoporosis: Sclerostin inhibition studied as a treatment for osteoporosis,
4. Accelerated fracture healing: Sclerostin inhibition accelerate fracture healing in animal models,
5. For other bone disorders: Sclerostin inhibition is also studied in osteogenesis imperfecta and bone metastases.
6. Potential cardiovascular benefits: sclerostin inhibition may have cardiovascular benefits though reducing calcification and improving cardiovascular function.
sclerostin inhibitors a new area of research, and more studies are needed to fully understand its therapeutic potential and safety profile..
1. Fgf23 is increased mainly from osteocyte early on in CKD due to hyperphosphatemia. It tries to compensate it through exercising a phosphaturic effect, decreasing the reabsorption of phosphat in renal tubule.
It is hypothesized early that this is his main adaptive function.
Later on, it is suggested that this may also be maladaptive due to increased Fgf23 even in the presence of relative hypophosphatemia. Some experts thinks that the downregulation of alpha klotho cofactor contribute to further increasing in fgf23 in Order to maintain its function on kidney.
Other experts suggest that there in decreased catabolism of fgf23 in CKD patients leading to high level of uncatabolised Fgf23.
It is suggested that there is osteocytes- overexpression of fgf23 on their surface due to maladaptive dysfunction of DMP1 (an inhibitor of fgf23).
Effects of fgf23 is divided to kotho dependent and klotho – independent:
Klotho dependent effects are inhibition of phosphat reabsorption from kidney what cause phosphaturic effect and inhibition of PTH secretion and it inhibit the production of 1,25 OH vitamin D.
Alpha kotho independent mechanism of fgf23 is left ventricular hypertrophy.
It is important to mention that epidemiological data about direct relationship between Fgf23 and arterial calcification are conflicting. Other study showed that reduction of fgf23 with phosphate binders lead to improvement in endothelial dysfunction (measurements of flow mediated vasodilation).
2.Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Wnt inhibitor sklerostin is considered as a high selective Wnt pathway inhibitor ( in contrast to DKK1 which considered as a panwnt inhibitor).
Wnt pathway activation lead to increased activation and differentiation of osteoblasts and bone gain. So , sclerostin through inhibition of wnt pathway, it will lead to decreased activation of osteoblasts and the balance of bone will shift toward osteoclasts.
Increased sclerostin lead to increased bone resorption and decreased mineralization.
The increased sclerostin level may be due to overproduction or decreased catabolism. It sill unclear.
The relationship between sclerostin and bone turnover is inversed.
It is important to mention that sclerostin overexpression lead to increased bone resistance to PTH.
On vascular system there is evidence of increased overexpression of sclerostin in calcified arteries and valves in relation to non calcified.
3.Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
The regulators of osteocalcin are : PTH and vitamin D. Both increase the level of osteocalcin secretion from osteoblasts through acting on PTHreceptors and activation of cAMP signaling pathway and vitamin D promoters site in BGLAP gene respectively.
The main factor for carboxylation of osteocalcin is vitamin K. The carboxylized form is the active form.
It is thought that the percentage of carboxylized to non carboxylized form of osteocalcin is 50%.
In context of vitamin K deficency and CKD ,high PTH and uremic toxin and deranged concentration of PTH there is an increased level of uncarboxylized osteocalcin. Uncarboxylized osteocalcin has negative effects on glucose metabolism leading to high insulin resistance and state of insulin deficiency, promoting cardiovascular calcification.
4.Discuss the role of bone morphogenic proteins in vascular calcification.
It is suggested that there is a dysregulation between BMP2 andBMP7, mostly studied in CKD-MBD. This dysbalance can lead to vascular calcification.
BMP2 is a inductor of smooth muscle calcification and is overexpressed in calcified vessel it upregulate natrium phosphate cotronsporter in smooth muscle cells leading to increased calcification.
On the other hand, BMP7 has inhibitory effect on vascular smooth muscle and are in CKD patient underexpressed.
1- FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and mal-adaptive effects on kidney, heart, and parathyroid glands.
the most prominent, bone-derived factor that is clearly abnormally elevated in CKD
IS FGF23 The osteocyte is main production site in bone
(Although the kidney, the liver, and coronary arteries have been suggested as sources of this factor)
α-klotho a cofactor, is needed for FGF23 to bind to receptors
The physiological role of FGF23 is to maintain balance of phosphorus and vitamin D
In CKD with loss of nephron
Decreases phosphorus reabsorption and excretion leading to hyperphosphatemia
FGF23 maintain balance and has adaptive phosphaturic effect
And keep plasma concentrations of phosphate close to normal
Other physiological actions of FGF23 are to reduce production and secretion of parathyroid hormone, and interference with metabolism of vitamin D, leading to a fall in the concentration of 1,25-dihydroxycholecalciferol
The maladaptive increase of FGF23 due to many suggestions
# CKD inhibits FGF23 catabolism.
# a relative resistance to its renal effects, possibly due to downregulation of tissue α-klotho, a cofactor for FGF23 signaling
The maladaptive) increases in FGF23 concentrations are directly involved in the dismal clinical outcome in CKD. Findings from observational studies
showed increased mortality with elevated concentrations of FGF23 in all stages of CKD, including after transplantation
association of cardiovascular diseases and FGF23
in addition the prevalence of LVH IS strongly associated with increase FGF23 concentration
FGF23-independent effects:
Antioxidant
Vasoprotective
Anticalcifying
Phosphaturia
α-klotho-independent effect:
Left ventricular hypertrophy
1. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system.
Wnt inhibitors are secreted factors that interact with Wnt receptors or Wnt ligands and attenuate Wnt signalling activity (( Wnt signalling pathways play a key part in many diverse biological processes, such as cell proliferation, growth, migration, and differentiation))
Wnt signalling (including soluble inhibitors) has a key role in bone physiology and regulation of bone cellular activities and mineralisation processes.
For example of Wnt inhibitors
sclerostin and Dickkopf (Dkk1) both protein are soluble Wnt inhibitor
the effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system
bone dysregulation and induction adynamic bone disease
inhibit osteoblast activity and decrease bon formation
in addition the impact of calcified aortic valve
# Sclerostin expression has also been shown in calcifying vascular smooth-muscle cells in vitro.
And detectable in calciphylaxis cases
Occurrence of sclerostin in calcified tissue is also
2. Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
It is regulated by the two major mineral and bone-controlling hormones
vitamin D and parathyroid hormone
Osteocalcin expression by the BGLAP gene and production are directly stimulated by vitamin D through a vitamin-D-responsive element located in the promoter region of BGLAP.
Parathyroid hormone also stimulates osteocalcin production through its binding to the receptor PTH1R and activation of the cAMP-dependent proteinkinase-A intracellular signalling pathway
There are two forms of osteocalcine
1-carboxylated form ( active form ) γ-carboxylated form
acts as a regulator of bone mineralisation, affecting hydroxyapatite size and shape, and is a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form
2-uncarboxylated form
Uncarboxylated (or undercarboxylated) forms of osteocalcin that are not bound to hydroxyapatite are released into the bloodstream, where they accumulate with fragments derived from direct proteolysis of osteocalcin after bone resorption, to constitute circulating osteocalcin
# account for up to 50% of total osteocalcin in serum samples from normal people
# its concentration affected by vit. K Status and degree of bonr remodling in CKD or in ESRD on dialysis
Osteocalcin in chronic kidney disease
Under conditions of normal kidney function and the absence of vitamin K deficiency, the proportion of uncarboxylated osteocalcin is low, stimulating insulin secretion and improving insulin sensitivity and energy handling. In the setting of chronic kidney disease or vitamin K deficiency, the amount of uncarboxylated osteocalcin increases, and as such negatively affects insulin secretion and sensitivity, promoting cardiovascular disease. Chronic kidney disease has a direct calcifying effect, not mediated by bone, and additionally vitamin K deficiency can also negatively affect the carboxylation status of matrix gla protein
3. Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins have a role in several clinical disorders ranging from vascular calcification
(Rennenberg RJ, Schurgers LJ, Kroon AA, Stehouwer CD. Arterial calcifications. J Cell Mol Med 2010; 14: 2203–10 )
to obesity, diabetes, and cancer. ( Kim M, Choe S. BMPs and their clinical potentials. BMB Rep 2011; 44: 619–34)
the bone morphogenetic proteins considered additional factors related to bon derived factors involved in vascular calcification
need more study and researches support this suggestion
1.FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on kidney, heart, and parathyroid glands.
FGF-23-klotho is one of the most extensively studied pathways in CKD due to its wide-reaching effects on the kidney, heart, and parathyroid glands.
On a physiological level, FGF-23-klotho reduces the production and secretion of parathyroid hormone and reduces the production of vitamin D which can lead to reduced calcium absorption in the kidneys and increased calcium levels in the blood.
In the heart, FGF-23 can have both adaptive and maladaptive effects.
Adaptive effects include reducing the risk of left ventricular hypertrophy, which is a condition that can lead to heart failure.
Maladaptive effects include increasing the risk of arterial calcification and vascular damage, which can worsen the effects of CKD.
2. Wnt-inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on bone and cardiovascular system
Sclerostin is a Wnt inhibitor because it is almost exclusively bone derived. It acts as an inhibitor of the Wnt-catenin pathway and also has suppressive effects on bone morphogenic proteins. Sclerostin can interfere with systems for biological signalling that operate in the vessel wall and has been found to be upregulated in calcified aortic valves of patients undergoing haemodialysis. Disturbed Wnt signalling could be particularly relevant in adynamic bone disease that is characterised by low bone turnover. In addition, increased concentrations of bone-derived Wnt inhibitors (eg, sclerostin) in CKD could interfere with atherosclerosis, as Wnt signalling has a crucial role in human atherosclerosis.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Osteocalcin is involved in the regulation of bone mineralisation, affecting hydroxyapatite size and shape, and is a potential modulator of osteoblast and osteoclast activities through its vitamin-K-dependent γ-carboxylated form.
The secretion of osteocalcin is regulated by PTH. PTH stimulates the production of osteocalcin by binding to the receptor PTH1R and activation in the cAMP-dependent protein-kinase-A intracellular signalling pathway.
The carboxylation of osteocalcin is regulated by vitamin K, which is necessary for the conversion of undercarboxylated osteocalcin to its carboxylated form.
Vitamin K is required for the γ-carboxylation of glutamate residues in the N-terminal domain of osteocalcin. Vitamin K deficiency or chronic kidney disease can result in an increase in the proportion of uncarboxylated osteocalcin, resulting in decreased insulin sensitivity and increased cardiovascular risk.
Discuss the role of bone morphogenic proteins in vascular calcification.
Bone morphogenetic proteins (BMPs) are a family of proteins that are involved in a variety of biological functions, including the regulation of bone formation, cell differentiation, and vascular calcification.
BMP2 and BMP7 have both been extensively studied in relation to experimental vascular calcification.
BMP2 stimulates the osteoregulatory gene MSX2 and enhances phosphate uptake through upregulation of the type III sodium-dependent phosphate co-transporter in vascular smooth-muscle calcification.
BMP2 expression is increased in arterial calcification, and BMP7 overexpression suppresses vascular calcification in experimental animal models.
BMP2 and BMP7 may have a role in vascular calcification, either directly or through the modulation of other factors in the calcification process.
BMPs play an important role in the regulation of vascular calcification, and an imbalance in their levels can result in an increased risk of vascular calcification in chronic kidney disease.
FGF-23-klotho is one of the most extensively studied pathways in CKD. Explain its adaptive and maladaptive effects on the kidney, heart, and parathyroid glands.
FGF23 escapes physiological control in CKD, according to many studies. Phosphorus balance may regulate FGF23 in physiology. However, elevated FGF23 concentrations and mild hypophosphatemia in early-stage CKD imply a maladaptive rise owing to an undiscovered CKD cause.
Oral phosphate-binding treatment has inconsistent effects on FGF23 concentrations, even when phosphorus intake or plasma concentrations are lowered, supporting maladaptive FGF23 increases.
Despite significant hypophosphatemia in many patients, FGF23 concentrations decline for many months following kidney transplantation, suggesting that CKD itself promotes FGF23. 23 FGF23 is favorably related to phosphate concentration again after transplantation, indicating the maladaptive rise disappears with time. In peritoneal dialysis patients, practically all circulating FGF23 was intact, unlike in healthy persons. CKD inhibits FGF23 catabolism.
Wnt inhibitors play an important role in the kidney-bone-vascular axis. Highlight the presumed effect of sclerostin, a soluble Wnt-inhibitor, on the bone and the cardiovascular system.
Sclerostin also inhibits bone-morphogenic proteins.
Sclerostosis, Van Buchem’s disease, and genetically engineered mouse models demonstrate Wnt signaling’s clinical importance for bone. Overexpression of both sclerostin and DKK1 decreases bone mass and strength in animal models. In animal studies, sclerostin affects bones through local Wnt pathways and parathyroid hormone. These findings demonstrate the need for balanced Wnt signaling for bone health. Due to elevated sclerostin levels, CKD may disrupt this action. However, these increased concentrations have mixed effects: Reduced osteocytic Wnt-β-catenin signaling was an early finding in experimental CKD-MBD, but monocytes from CKD patients have increased Wnt-catenin pathway activity. Circulating Wnt inhibitors impact vascular calcification due to vascular smooth-muscle cell death. The current study shows that calcified aortic valves of hemodialysis patients upregulated sclerostin mRNA more than non-calcified controls. Calcifying vascular smooth-muscle cells in vitro causes them to express sclerostin.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts. Discuss the regulators of osteocalcin secretion and carboxylation.
Through its vitamin-K-dependent carboxylated form, osteocalcin regulates bone mineralization and hydroxyapatite size and shape.
Uncarboxylated (or under-carboxylated) osteocalcin that is not bonded to hydroxyapatite is discharged into the circulation and accumulates with fragments from direct proteolysis during bone resorption to create circulating osteocalcin.
Uncarboxylated osteocalcin is predicted to contribute up to 50% of total osteocalcin in blood samples from normal adults, notwithstanding the variability of circulating osteocalcin fragments.
In patients with CKD and those on hemodialysis, total osteocalcin concentrations are positively correlated with histological parameters of bone remodeling and affected by vitamin K status.
Lee and colleagues proposed that circulating uncarboxylated osteocalcin acts as a hormone to improve insulin secretion and sensitivity and prevent animal obesity. Several epidemiological studies have indicated a negative relationship between total blood osteocalcin concentrations and glycemia, glucose metabolism, and obesity. However, few of these investigations have examined uncarboxylated forms of osteocalcin, and they have not found similar relationships with glucose or adiposity, unlike evidence from murine models.
This variation may be due to osteocalcin genetics (one gene in humans, three genes in mice), concentrations, and metabolism.
Another possibility is the complicated relationship between vitamin K and osteocalcin. Vitamin K supplementation decreases the uncarboxylated forms of osteocalcin, but the few human studies that have been done show that it has different effects on glucose metabolism. There are also no solid data about how the oral vitamin K antagonist warfarin affects energy metabolism.
Discuss the role of bone morphogenic proteins in vascular calcification.
Although not synthesized in bone, several bone morphogenetic proteins may be connected to the CKD-MBD disease due to their biochemical features. Experimental vascular calcification has focused on BMP2 and BMP7.
BMP2 increases phosphate absorption by upregulating the type III sodium-dependent phosphate co-transporter in vascular smooth-muscle calcification and the osteo-regulatory gene MSX2. Inflammation increases vessel wall BMP2 expression, which inhibits calcification through MGP and SMAD6.
BMP2 induces calcification, and CKD patients had higher BMP2 serum concentrations and higher vascular stiffness. Intriguingly, BMP2 is associated with decreased expression of smooth-muscle cell markers in vascular smooth-muscle calcification, which promotes the osteoblastic-like phenotype, while BMP7 promotes the phenotype of vascular smooth-muscle calcification and inhibits calcification, possibly implicating it in bone and vascular disease.
In renal disease models, BMP7 expression is significantly reduced in renal tissue, and circulatory BMP7 concentrations are low. BMP7 also prevents vascular calcification in experimental atherosclerosis, CKD, metabolic syndrome, and adynamic bone lesions.
BMP2 and BMP7 may protect podocytes from profibrotic stimuli and metabolically interact with SOST and DKK1 in bone.
BMP2 and BMP7’s relationship with calciprotein particles and arterial stiffness in CKD patients suggests systemic implications beyond these local cytokine-like effects.