Osteocyte are the protagonist in bone turnover process ;
– linkage between osteoclast and osteoblast and co ordination . -functions on cell surfaces on muscles and kidney. -increases the synthesis of FGF-23 in CKD.
-Osteocyte produces sclerostin which is Associated with a dynamic bone disease. it constitutes more than 90 % of all bone cells and it is able to respond to changes in hormones, and electrolytes.
In the last decades, osteocytes, have a prominent role in metabolic bone diseases.
Its important leader role in bone turnover, coordinating both osteoblasts and osteoclasts. Correspond to most of all bone cells, are able to respond to different factors load, hormones, and electrolytes, and act on different organ beside bone surface. For example acting on muscles by the production of proteins that regulate muscle mass, on pencrease by insulin secretion, on kidney causing phosphaturia, and synthesis of calcitriol and cytokines beside exhibit an increased synthesis of FGF-23 in CKD As FGF-23 increase from early kidney diseases and in CKD Klotho expression in osteocytes is about 500 times lower than in kidneys so these cells has important role in serum biochemistry, PTH, bone volume turnover. This innovative view of the pathophysiology of CKD-MBD should change the way we evaluate and treat bone and cardiovascular diseases in CKD patient
the osteoblast plays an important role in metabolic bone diseases.
— osteocytes works is mastermind of bone turn over. to correlate both osteoblast and osteoclasts. they are not only act on bones but also surface cells and other organs several clinical trials reveal osteocytes express the increase synthesis ofFGF23 in CKD
there are 3 main cells in our bone, but the manager is osteocyte which produce FGF-23 which is the corner stone of new trade off theory. FGF-23 accumulates pyrophosphate and osteopontin, which inhibit bone mineralization. FGF-23 STIMULATES Dickkopf-related protein1 which inhibit wnt pathway thus increase bone resorption and decrease bone formation
Osteocytes regulate local mineral deposition and chemistry at the bone matrix level, and they also function as endocrine cells producing factors that target distant organs such as the kidney to regulate phosphate transport. Osteocytes appear to be the major local orchestrator of many of bone’s functions.
The role of osteocyte signaling:
1. Regulation of local mineralization mediated by DMP1, PHEX, and MEPE.
2. Regulation of systemic mineralization: cross talk with other organs particularly the kidneys. One factor that is central to the regulation of the bone–kidney axis is the FGF-23.
FGF 23 regulated by PHEX, DMP1, and MEPE.
Sclerostin increases FGF23 by inhibiting PHEX.
3. Bone formation by osteoblasts; mediated by Sclerostin.
· Sclerostin: a soluble Wnt signaling antagonist and potent suppressor of bone formation. Burger EH et al. demonstrated that osteocytes are a major source of Wnt signaling antagonists, including DKK1 and Sclerostin.
Activation of the Wnt/β-catenin pathway promotes osteoblastogenesis by stimulating osteoblast differentiation and blocks apoptosis and osteoclastogenesis.
4. Bone resorption by osteoclasts; the identification of the RANK/RANKL/OPG pathway as the dominant final mediator of osteoclastogenesis.
5. Sensing mechanical loads on bone
Circulating levels of Sclerostin started to increase gradually as kidney function declines reported to be approximately 3–4 times higher in patients with end-stage renal failure.
In CKD osteocytes increased synthesis of FGF23.
Fang et al reported that, Wnt inhibitors are usually secreted during kidney injury. in CKD mouse models, in comparison with non-CKD diabetic controls, increased levels of Wnt inhibitors and Klotho were found in CKD and the use of a monoclonal antibody to reduce levels of Dkk1-enhanced bone formation rates. In their protocol, combination of the monoclonal antibody with phosphate binders was found to completely ameliorate the induced CKD-MBD.
Although there is not much evidence about the direct interaction of FGF23 or Klotho with Wnt elements, it has been shown that the extracellular domain of Klotho binds to multiple Wnt ligands, inhibiting their ability to activate Wnt signaling. There is data suggesting potential crosstalk between Wnt signaling and the regulation of Klotho and FGF23. Wang, Y. et al 
Therapeutic targeting of osteocytes and their derived factors (Sclerostin, RANKL, and FGF23) has proven to be an effective approach to treat common and rare bone diseases, as well as the deleterious effects of cancer in bone.
Osteocyte are the protagonist in bone turnover process:
-its linkage between osteoclast and osteoblast and co ordination
-Its function on cell surfaces on muscles and kidney
-it increases the synthesis of FGF-23 in CKD.
-Osteocyte produce sclerostin which is Associated with adynamic bone disease. it constitutes more than 90 % of all bone cells and it is able to respond to changes in hormones, and electrolytes.
1-Osteocytes, the most differentiated form of osteoblasts, have been recognized as playing a prominent role in metabolic bone diseases.
2-These cells also correspond to more than 90% of all bone cells, are able to respond to changes in the load, hormones, and electrolytes, and may act not only on bone surface cells but also on other organs, including muscles, pancreas, and kidneys. The action in other sites is mediated by the production of proteins that regulate muscle mass, insulin secretion, phosphaturia, and synthesis of calcitriol and cytokines.
3-Several experimental, observational, and even clinical trials have shown that osteocytes exhibit an increased synthesis of FGF-23 in CKD.
5-Indeed, Pereira et al. demonstrated increased expression of FGF-23, DMP-1, and MEPE in bone biopsies obtained from pediatric patients with CKD.
6-They also demonstrated that patients with higher expression of FGF-23 had an accumulation of osteoid, suggesting possible local action of FGF-23 on inhibiting mineralization.
7-In addition, experimental studies have shown that either FGF-23 excess or absence could inhibit bone mineralization through the accumulation of pyrophosphate or osteopontin, respectively .
8-Another unexpected direct mechanism of action for FGF-23 on the skeleton is via its interaction with Klotho. Recent studies have shown that the level of Klotho expression in osteocytes is about 500 times lower than in kidneys. Mice with an osteocyte-specific deletion of the Klotho gene exhibit normal Klotho expression in kidneys and parathyroid glands and have normal serum biochemistry. However, these animals have increased bone formation, bone volume, and osteoblast activity as compared with wild type mice.
9-The mechanism by which FGF-23 and Klotho inhibit bone formation would involve the stimulation of Dickkopf-related protein1 (DKK1), a Wnt pathway inhibitor. The activation of this pathway increases bone formation and decreases bone resorption.An increase in DKK1 mediated by FGF-23 and Klotho was also demonstrated in an experimental study with 5/6 nephrectomized rats that were fed with a high-phosphate diet.
10-Importantly, it seems that, as CKD progresses, inhibition of the Wnt pathway increases. 
11-In addition, sclerostin is recently presented as a new bone and vascular disease biomarker. This 22-kDa glycoprotein, secreted mainly by osteocytes, is a soluble inhibitor of the canonical Wnt pathway that has a pivotal role in bone biology and turnover. CKD patients are reported with higher levels of sclerostin, and levels decrease during dialysis. Sclerostin is associated with vascular calcification and CV risk in CKD, although data are still controversial. The question whether serum sclerostin has protective or deleterious role in CKD-MBD pathophysiology, and therefore in cardiovascular risk and overall mortality, is still open and needs to be answered.
Osteocytes, the most specialized type of osteoblasts, have recently been discovered to have a significant role in metabolic bone disordersThese cells also account for more than 90% of all bone cells, are able to react to changes in load, hormones, and electrolytes, and may act not just on bone surface cells but also on muscles, the pancreas, and the kidneys. Other areas of action are mediated by the synthesis of proteins that affect muscle growth, insulin secretion, phosphaturia, calcitriol and cytokine synthesis.FGF-23 production is enhanced in CKD osteocytes. FGF-23 can suppress local mineralization by osteoid accumulation. Experimental studies suggest that excess or deficiency of FGF-23 can interfere with bone mineralization by accumulating pyrophosphate or osteopontin.Sclerostin inhibits vascular calcification and has a deleterious effect on bone formation.
Osteocytes secrete FGF23 and RANK1L which activate osteoclast. The role of FGF23 is multiple in terms of reducing phosphate and decreased bone mineralisation. Another role of FGF23 with klotho factor Is activation Wnt pathway inhibitor leading to bone demineralization. DMP1 and PHEX are osteocyte protein modulated by in response to increase FGF23 as per a study. Another therapy called Romosozumab (antibody to anti sclerostin have been used in women with osteoporosis and only one trial showed increased risk of cardiovascular events. . the basis of using this drug is that sclerostin as serum and bone marker is higher in patients on Haemodialysis who had fractures suggesting that blocking this drug may improve bone formation and mineralisation.
Osteocytes work as the true orchestrators of bone turnover by coordinating both osteoblasts and osteoclasts.
Osteocytes respond to changes in the load , hormones , and electrolytes.
Not only act on bone surface cells but also on remote organs like muscles, pancreas and kidneys by the action of proteins produced by it.
It also exhibits an increase synthesis of FGF-23 in CKD which has possible local action on inhibiting mineralization.
FGF-23 also interacted with klotho and inhibit bone formation .
W nt pathway inhition in CKD patients associated with increased bone expression of sclerostin with adynamic bone disease.and also in high bone turnover.
The osteocyte are the most differentiated form of osteoblast coordinate the activity of osteoblast and osteoclast, it is action not only on the bone but also on muscle, pancreas and kidney
In ckd the osteocyte causes increase in FGF – 23
In pediatric patients show increase also of DMP1and MEPE
A study show excess or decrease in FGF23 will cause inhibition of bone mineralization through production of Pyro phosphote and osteopontin in addition to direct effects of FGF23 on the bone through interaction with klotho which inhibit bone formation by stimulation of DKK1 (wnt pathway inhibitor) (the activation of this pathway will increase bone formation and decrease bone resorption.
Previously believed that DMP1 and PHEX (osteocyte specific protein) will cause decrease in the local FGF23 expression but now this change and their secretion due to compensatory mechanism to rise in FGF23.
Different studies in peritoneal dialysis show increase bone expression of sclerostin which causes decrease bone formation , in HD patients with SHPT and fracture show higher expression of sclerostin and lower bone formation with mineralization defects
So inhibition of sclerostin lead to improve bone remodeling and volume in ckd and decrease fracture risk.
After the use of romosuzumab which monoclonal ab sclerostin blockade to treat osteoporosis in woman show increases in cardiac events which not seen in other study, so the question now if sclerostin blockade lead to increase in vascular calcification progression??
The main orchestrator of bone turnover is a metabolic bone disease.
The maestro of all cells, osteoblast, and osteoclast.
It responds to metabolic and electrolyte changes.
Osteocytes, show an increased synthesis of FGF-23 in CKD.
This view shows the pathophysiology of CKD-MBD should change the metabolic bone disease and associated CKD risk factors (CVD).
Early CKD in reverse to the past suggestion associated with an increase in FGF-23, with associated mineralization inhibition.
FGF-23 excess inhibits bone mineralization by the accumulation of pyrophosphate.
FGF-23 absence inhibits bone mineralization by the accumulation of osteoportin.
Klotho and FGF-23:
Level of expression in osteocytes is 500 times lower than in kidneys.
Normal Klotho expression led to normal bone formation, volume, and osteoblast activity.
Klotho and FGF-23 inhibit bone formation by stimulation of Dickkopf-related protein-1 (DKK1), a W nt pathway inhibitor.
DKK1 activation under the effect of Klotho and FGF-23 leads to bone formation and reduces bone resorption.
There was an association between osteodystrophy and defect in W nt pathway.
Sclerostin is shown to have a higher level in the fractured patient, while the reverse in non-fractured patients, by a retrospective study of SHPT patients on hemodialysis.
Studies noted that CKD progression leads to inhibition of W nt pathway, this led to the suggestion that inhibition of sclerostin leads to improving both bone remodeling and volume, and therefore reduces fracture incidence.
One study noted that monoclonal anti-sclerostin antibodies increase the risk of CV events in osteoporosis women, while all other studies did not notice such an outcome.
Well done Dr. Kamal. In addition to your answer, there are two osteocyte-specific proteins, DMP1 and PHEX, that can negatively regulate local FGF-23 expression.
Osteocyte is differentiated cell from Osteoblast. It plays an essential role in MBD.
It is considered the protagonist in bone turnover process due to the following:
– Coordinate Osteoblast and osteoclast activities.
Respond to changes in the load, hormones, and electrolytes.
Act on cell surfaces on muscles, pancreas, and kidney
Produces proteins to regular bone and other sites:
FGF-23
Bind to Klotho leading to Inhibition of bone mineralization and increase osteoid formation by enhancing DKK1 production and Wnt pathway inhibition.
Increase phosphate excretion
Inhibits alpha hydroxylase leading to low 1-25 vit D
Increase Sclerostin expression in cortical bone as CKD progression causing higher inhibition of Wnt pathway and leading to lower bone formation, and greater mineralization defect.
How is the osteocyte the protagonist in the pathophysiology of CKD-MBD?
it constitutes more than 90 % of all bone cells and it is able to respond to changes in load, hormones, and electrolytes.
it coordinates both osteoblast and osteoclast cells. therefore it is the true orchestrator of bone turnover.
it acts on other organs as muscles, pancreas, and kidneys by the production of mediators that regulate muscle mass, insulin secretion, and serum phosphate.
1– Primary HPT increase inflammatory response . 2- increase synthesis of TNF and some inflammatory cytokines that
a- amplifies the osteoclastogenic .
b- resorption activity of the receptor activator of B ligand ( RANKL).
activation of immune cells promote bone destruction by stimulating bone resorbing osteoclasts.
the osteocytes most differentiated cell and coordinate both osteoblast and osteoclast and even induce bone formation out side the bone tissue .
these cell can progenotes the FGF23 and other proteins like DKKI and DMPI thats proteins cause inflammatory cytokines and promote action of FGF23 and induce calcifications even out side bone like in blood vessels and muscle
on the other hand kolotho expression in theses cell lower than the kidney and in some experimental trial in ckd mice the lower level of koltho stop new bone formation with increase level of FGF23 cause more damage and more increase in PTH
The osteocytes plain the main role in dealing with metabolic bone disease( the orchestrators).Several trails consolidate that osteocytes can increase level of FGF23 in CKD patients .This innovative view will change the way we evaluate the bone and cardiovascular disease in CKD .
As CKD progress GFF -23 increase ,this was demontrated by Pereia .et in bone biopsies obtained from pediatrics patients with CKD,Local Action of FGF23 inhibit mineralization of bone , and through accumulation of pyrophosphate and osteopontin.
As CKD progress the FG-F 23 is increased and Kolotho decrease and both of this changes will increase ,Recent stud- ies have shown that the level of Klotho expression in osteo- cytes is about 500 times lower than in kidneys
Thanks Dr. Rihab. In addition to your answer, there are two osteocyte-specific proteins, DMP1 and PHEX, that can negatively regulate local FGF-23 expression. Furthermore, high levels of sclerostin, produced by osteocyte, is associated with bone diseases in CKD.
Osteocytes are endocrine and bone cells . They secrete FGF23 .
1. There is a Associations between serum FGF23 level and vascular dysfunction, vascular calcification, and increased risk of cardiovascular disease( Cardiac hypertrophy). 2. The osteocyte can secrete RANKL and activate osteoclasts 3. The secretion of FGF23, will maintain phosphat balance (phosphaturic hormone). 4. Local Action of FGF23 inhibit mineralization of bone , and through accumulation of pyrophosphate and osteopontin. 5.FGF23 interact with klotho factor in bone and together will activate Wnt pathway inhibitor (called DKK), which inhibit bone mineralization. This WNT inhibitory pathway will be stronger with progression of CKD.
6 . There is a gene suppression of DMP1 and PHEX secondary to fgf23 production from osteocytes.
7.Beside of FGF23, another hormone called Sclerostin negatively affected bone formation by inhibition of wnt pathway too.
– there is a suggestion that sclerostin inhibit vascular calcification . And new therapy that antagonise this hormone like romosozumab are associated with increased risk of vascular death
Osteocytes, the kind of osteoblasts that has undergone the greatest differentiation, have been identified as having a significant impact on metabolic bone disorders.
In patients with chronic kidney disease (CKD), osteocytes have been found in a number of studies—both experimental and observational, as well as clinical—to produce more FGF-23.
Osteocytes, which seem to act as the actual orchestrators of bone turnover by coordinating the activities of osteoblasts and osteoclasts, are thought to be responsible for this process.
These cells also make up more than 90 percent of all bone cells, have the ability to react to changes in load, hormones, and electrolytes, and may act not just on the surface cells of the bone but also on other organs such as the muscles, pancreas, and kidneys.
The generation of proteins that affect muscle mass, insulin secretion, phosphaturia, and the synthesis of calcitriol and cytokines is what mediates the effect at other locations.
FGF-23 may impede mineralization locally by accumulating osteoid. Experimental investigations have revealed that FGF-23 excess or absence may impede bone mineralization by accumulating pyrophosphate or osteopontin.
FGF-23 directly affects the skeleton through Klotho. Recent investigations demonstrate that osteocytes express Klotho 500 times less than kidneys.
Well done Dr. Weam. In addition, DMP1 and PHEX, which are two osteocyte-specific proteins, can negatively regulate local FGF-23 expression. Also, Increased levels of sclerostin, produced by osteocyte, is associated with bone diseases in CKD.
Osteocytes, through the synthesis of FGF-23, orchestrate bone formation. It also produces DMP1, PHEX, and sclerostin which affect bone formation
Osteocyte are the protagonist in bone turnover process ;
– linkage between osteoclast and osteoblast and co ordination .
-functions on cell surfaces on muscles and kidney.
-increases the synthesis of FGF-23 in CKD.
-Osteocyte produces sclerostin which is Associated with a dynamic bone disease. it constitutes more than 90 % of all bone cells and it is able to respond to changes in hormones, and electrolytes.
In the last decades, osteocytes, have a prominent role in metabolic bone diseases.
Its important leader role in bone turnover, coordinating both osteoblasts and osteoclasts.
Correspond to most of all bone cells, are able to respond to different factors load, hormones, and electrolytes, and act on different organ beside bone surface.
For example acting on muscles by the production of proteins that regulate muscle mass, on pencrease by insulin secretion, on kidney causing phosphaturia, and synthesis of calcitriol and cytokines beside exhibit an increased synthesis of
FGF-23 in CKD
As FGF-23 increase from early kidney diseases and in CKD Klotho expression in osteocytes is about 500 times lower than in kidneys so these cells has important role in serum biochemistry, PTH, bone volume turnover.
This innovative view of the pathophysiology of CKD-MBD should change the way we evaluate and treat bone and cardiovascular diseases in CKD patient
the osteoblast plays an important role in metabolic bone diseases.
— osteocytes works is mastermind of bone turn over. to correlate both osteoblast and osteoclasts. they are not only act on bones but also surface cells and other organs several clinical trials reveal osteocytes express the increase synthesis ofFGF23 in CKD
there are 3 main cells in our bone, but the manager is osteocyte which produce FGF-23 which is the corner stone of new trade off theory. FGF-23 accumulates pyrophosphate and osteopontin, which inhibit bone mineralization. FGF-23 STIMULATES Dickkopf-related protein1 which inhibit wnt pathway thus increase bone resorption and decrease bone formation
Thanks Dr. Ahmed for your answer. That is in addition to actions of DMP1, PHEX, and sclerostin, which are produced by osteocytes, on bone.
Osteocytes regulate local mineral deposition and chemistry at the bone matrix level, and they also function as endocrine cells producing factors that target distant organs such as the kidney to regulate phosphate transport. Osteocytes appear to be the major local orchestrator of many of bone’s functions.
The role of osteocyte signaling:
1. Regulation of local mineralization mediated by DMP1, PHEX, and MEPE.
2. Regulation of systemic mineralization: cross talk with other organs particularly the kidneys. One factor that is central to the regulation of the bone–kidney axis is the FGF-23.
FGF 23 regulated by PHEX, DMP1, and MEPE.
Sclerostin increases FGF23 by inhibiting PHEX.
3. Bone formation by osteoblasts; mediated by Sclerostin.
· Sclerostin: a soluble Wnt signaling antagonist and potent suppressor of bone formation.
Burger EH et al. demonstrated that osteocytes are a major source of Wnt signaling antagonists, including DKK1 and Sclerostin.
Activation of the Wnt/β-catenin pathway promotes osteoblastogenesis by stimulating osteoblast differentiation and blocks apoptosis and osteoclastogenesis.
4. Bone resorption by osteoclasts; the identification of the RANK/RANKL/OPG pathway as the dominant final mediator of osteoclastogenesis.
5. Sensing mechanical loads on bone
Circulating levels of Sclerostin started to increase gradually as kidney function declines reported to be approximately 3–4 times higher in patients with end-stage renal failure.
In CKD osteocytes increased synthesis of FGF23.
Fang et al reported that, Wnt inhibitors are usually secreted during kidney injury. in CKD mouse models, in comparison with non-CKD diabetic controls, increased levels of Wnt inhibitors and Klotho were found in CKD and the use of a monoclonal antibody to reduce levels of Dkk1-enhanced bone formation rates. In their protocol, combination of the monoclonal antibody with phosphate binders was found to completely ameliorate the induced CKD-MBD.
Although there is not much evidence about the direct interaction of FGF23 or Klotho with Wnt elements, it has been shown that the extracellular domain of Klotho binds to multiple Wnt ligands, inhibiting their ability to activate Wnt signaling. There is data suggesting potential crosstalk between Wnt signaling and the regulation of Klotho and FGF23. Wang, Y. et al

Therapeutic targeting of osteocytes and their derived factors (Sclerostin, RANKL, and FGF23) has proven to be an effective approach to treat common and rare bone diseases, as well as the deleterious effects of cancer in bone.
Great explanation. Thank you Dr. Amna
Osteocyte are the protagonist in bone turnover process:
-its linkage between osteoclast and osteoblast and co ordination
-Its function on cell surfaces on muscles and kidney
-it increases the synthesis of FGF-23 in CKD.
-Osteocyte produce sclerostin which is Associated with adynamic bone disease. it constitutes more than 90 % of all bone cells and it is able to respond to changes in hormones, and electrolytes.
Good answer. Thanks Dr. Mahmoud.
1-Osteocytes, the most differentiated form of osteoblasts, have been recognized as playing a prominent role in metabolic bone diseases.
2-These cells also correspond to more than 90% of all bone cells, are able to respond to changes in the load, hormones, and electrolytes, and may act not only on bone surface cells but also on other organs, including muscles, pancreas, and kidneys. The action in other sites is mediated by the production of proteins that regulate muscle mass, insulin secretion, phosphaturia, and synthesis of calcitriol and cytokines.
3-Several experimental, observational, and even clinical trials have shown that osteocytes exhibit an increased synthesis of FGF-23 in CKD.
5-Indeed, Pereira et al. demonstrated increased expression of FGF-23, DMP-1, and MEPE in bone biopsies obtained from pediatric patients with CKD.
6-They also demonstrated that patients with higher expression of FGF-23 had an accumulation of osteoid, suggesting possible local action of FGF-23 on inhibiting mineralization.
7-In addition, experimental studies have shown that either FGF-23 excess or absence could inhibit bone mineralization through the accumulation of pyrophosphate or osteopontin, respectively .
8-Another unexpected direct mechanism of action for FGF-23 on the skeleton is via its interaction with Klotho. Recent studies have shown that the level of Klotho expression in osteocytes is about 500 times lower than in kidneys. Mice with an osteocyte-specific deletion of the Klotho gene exhibit normal Klotho expression in kidneys and parathyroid glands and have normal serum biochemistry. However, these animals have increased bone formation, bone volume, and osteoblast activity as compared with wild type mice.
9-The mechanism by which FGF-23 and Klotho inhibit bone formation would involve the stimulation of Dickkopf-related protein1 (DKK1), a Wnt pathway inhibitor. The activation of this pathway increases bone formation and decreases bone resorption.An increase in DKK1 mediated by FGF-23 and Klotho was also demonstrated in an experimental study with 5/6 nephrectomized rats that were fed with a high-phosphate diet.
10-Importantly, it seems that, as CKD progresses, inhibition of the Wnt pathway increases.

11-In addition, sclerostin is recently presented as a new bone and vascular disease biomarker. This 22-kDa glycoprotein, secreted mainly by osteocytes, is a soluble inhibitor of the canonical Wnt pathway that has a pivotal role in bone biology and turnover. CKD patients are reported with higher levels of sclerostin, and levels decrease during dialysis. Sclerostin is associated with vascular calcification and CV risk in CKD, although data are still controversial. The question whether serum sclerostin has protective or deleterious role in CKD-MBD pathophysiology, and therefore in cardiovascular risk and overall mortality, is still open and needs to be answered.
Good answer Dr. Alaa.
Osteocytes, the most specialized type of osteoblasts, have recently been discovered to have a significant role in metabolic bone disordersThese cells also account for more than 90% of all bone cells, are able to react to changes in load, hormones, and electrolytes, and may act not just on bone surface cells but also on muscles, the pancreas, and the kidneys. Other areas of action are mediated by the synthesis of proteins that affect muscle growth, insulin secretion, phosphaturia, calcitriol and cytokine synthesis.FGF-23 production is enhanced in CKD osteocytes. FGF-23 can suppress local mineralization by osteoid accumulation. Experimental studies suggest that excess or deficiency of FGF-23 can interfere with bone mineralization by accumulating pyrophosphate or osteopontin.Sclerostin inhibits vascular calcification and has a deleterious effect on bone formation.
Thanks Dr. Rania. That is in addition to actions of DMP1, PHEX, and sclerostin, which are produced by osteocytes, on bone.
Osteocytes secrete FGF23 and RANK1L which activate osteoclast. The role of FGF23 is multiple in terms of reducing phosphate and decreased bone mineralisation. Another role of FGF23 with klotho factor Is activation Wnt pathway inhibitor leading to bone demineralization. DMP1 and PHEX are osteocyte protein modulated by in response to increase FGF23 as per a study. Another therapy called Romosozumab (antibody to anti sclerostin have been used in women with osteoporosis and only one trial showed increased risk of cardiovascular events. . the basis of using this drug is that sclerostin as serum and bone marker is higher in patients on Haemodialysis who had fractures suggesting that blocking this drug may improve bone formation and mineralisation.
Good answer Dr. Muhammad. additionally, osteocytes work as the true orchestrators of bone turnover by coordinating both osteoblasts and osteoclasts.
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Osteocytes work as the true orchestrators of bone turnover by coordinating both osteoblasts and osteoclasts.
Osteocytes respond to changes in the load , hormones , and electrolytes.
Not only act on bone surface cells but also on remote organs like muscles, pancreas and kidneys by the action of proteins produced by it.
It also exhibits an increase synthesis of FGF-23 in CKD which has possible local action on inhibiting mineralization.
FGF-23 also interacted with klotho and inhibit bone formation .
W nt pathway inhition in CKD patients associated with increased bone expression of sclerostin with adynamic bone disease.and also in high bone turnover.
Good answer Dr. Asmaa. Do not forget also DMP1, PHEX, and sclerostin which are produced by osteocytes.
The osteocyte are the most differentiated form of osteoblast coordinate the activity of osteoblast and osteoclast, it is action not only on the bone but also on muscle, pancreas and kidney
In ckd the osteocyte causes increase in FGF – 23
In pediatric patients show increase also of DMP1and MEPE
A study show excess or decrease in FGF23 will cause inhibition of bone mineralization through production of Pyro phosphote and osteopontin in addition to direct effects of FGF23 on the bone through interaction with klotho which inhibit bone formation by stimulation of DKK1 (wnt pathway inhibitor) (the activation of this pathway will increase bone formation and decrease bone resorption.
Previously believed that DMP1 and PHEX (osteocyte specific protein) will cause decrease in the local FGF23 expression but now this change and their secretion due to compensatory mechanism to rise in FGF23.
Different studies in peritoneal dialysis show increase bone expression of sclerostin which causes decrease bone formation , in HD patients with SHPT and fracture show higher expression of sclerostin and lower bone formation with mineralization defects
So inhibition of sclerostin lead to improve bone remodeling and volume in ckd and decrease fracture risk.
After the use of romosuzumab which monoclonal ab sclerostin blockade to treat osteoporosis in woman show increases in cardiac events which not seen in other study, so the question now if sclerostin blockade lead to increase in vascular calcification progression??
Good job.
Osteocyte: the protagonist:
Klotho and FGF-23:
Good job.
Well done Dr. Kamal. In addition to your answer, there are two osteocyte-specific proteins, DMP1 and PHEX, that can negatively regulate local FGF-23 expression.
Osteocytes work as true orchestrators of bone turnover coordinating both osteoblasts and osteoblast .
Thanks Dr. Ashraf. Do not forget also DMP1, PHEX, and sclerostin which are produced by osteocytes.
Osteocyte is differentiated cell from Osteoblast. It plays an essential role in MBD.
It is considered the protagonist in bone turnover process due to the following:
– Coordinate Osteoblast and osteoclast activities.
Great explanation. Thank Dr. Asma
How is the osteocyte the protagonist in the pathophysiology of CKD-MBD?
Good job Dr. Ibrahim. That is in addition to actions of DMP1, PHEX, and sclerostin.
1– Primary HPT increase inflammatory response .
2- increase synthesis of TNF and some inflammatory cytokines that
a- amplifies the osteoclastogenic .
b- resorption activity of the receptor activator of B ligand ( RANKL).
activation of immune cells promote bone destruction by stimulating bone resorbing osteoclasts.
This is not the answer for this question Dr. Ashraf
the osteocytes most differentiated cell and coordinate both osteoblast and osteoclast and even induce bone formation out side the bone tissue .
these cell can progenotes the FGF23 and other proteins like DKKI and DMPI thats proteins cause inflammatory cytokines and promote action of FGF23 and induce calcifications even out side bone like in blood vessels and muscle
on the other hand kolotho expression in theses cell lower than the kidney and in some experimental trial in ckd mice the lower level of koltho stop new bone formation with increase level of FGF23 cause more damage and more increase in PTH
Great job Dr. Rabab.
That in addition to DMP1, PHEX, and sclerostin, produced by osteocytes, which are associated with bone abnormalities in CKD.
The osteocytes plain the main role in dealing with metabolic bone disease( the orchestrators).Several trails consolidate that osteocytes can increase level of FGF23 in CKD patients .This innovative view will change the way we evaluate the bone and cardiovascular disease in CKD .
As CKD progress GFF -23 increase ,this was demontrated by Pereia .et in bone biopsies obtained from pediatrics patients with CKD,Local Action of FGF23 inhibit mineralization of bone , and through accumulation of pyrophosphate and osteopontin.
As CKD progress the FG-F 23 is increased and Kolotho decrease and both of this changes will increase ,Recent stud-
ies have shown that the level of Klotho expression in osteo-
cytes is about 500 times lower than in kidneys
Thanks Dr. Rihab. In addition to your answer, there are two osteocyte-specific proteins, DMP1 and PHEX, that can negatively regulate local FGF-23 expression. Furthermore, high levels of sclerostin, produced by osteocyte, is associated with bone diseases in CKD.
Osteocytes are endocrine and bone cells . They secrete FGF23 .
1. There is a Associations between serum FGF23 level and vascular dysfunction, vascular calcification, and increased risk of cardiovascular disease( Cardiac hypertrophy).
2. The osteocyte can secrete RANKL and activate osteoclasts
3. The secretion of FGF23, will maintain phosphat balance (phosphaturic hormone).
4. Local Action of FGF23 inhibit mineralization of bone , and through accumulation of pyrophosphate and osteopontin.
5.FGF23 interact with klotho factor in bone and together will activate Wnt pathway inhibitor (called DKK), which inhibit bone mineralization. This WNT inhibitory pathway will be stronger with progression of CKD.
6 . There is a gene suppression of DMP1 and PHEX secondary to fgf23 production from osteocytes.
7.Beside of FGF23, another hormone called Sclerostin negatively affected bone formation by inhibition of wnt pathway too.
– there is a suggestion that sclerostin inhibit vascular calcification . And new therapy that antagonise this hormone like romosozumab are associated with increased risk of vascular death
Good job.
Osteocyte: the protagonist
Osteocyte produce FGF-23: The first lab abnormalities in CKD-MBD
Osteocyte produce sclerostin:
Osteocyte is a mechanoreceptor
Osteocyte is a stress sensing
Osteocyte produce other proteins as well e.g activin A, RANKL, OPG
Great Answer, Dr. Ben. Do not forget that two osteocyte-specific proteins, DMP1 and PHEX, can negatively regulate local FGF-23 expression.
Good job.
Well done Dr. Weam. In addition, DMP1 and PHEX, which are two osteocyte-specific proteins, can negatively regulate local FGF-23 expression. Also, Increased levels of sclerostin, produced by osteocyte, is associated with bone diseases in CKD.