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Vascular calcification and renal bone disorders.

Lu KC, Wu CC, Yen JF, Liu WC - ScientificWorldJournal (2014)

Bottom Line: Besides, CKD patients usually suffer from vascular calcification (VC), which is highly associated with mortality.These factors have roles in both promoting and inhibiting VC.In addition, the calcified vessel may secrete FGF23 and Wnt inhibitors such as sclerostin, DKK-1, and secreted frizzled-related protein to prevent further VC.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan.

ABSTRACT
At the early stage of chronic kidney disease (CKD), the systemic mineral metabolism and bone composition start to change. This alteration is known as chronic kidney disease-mineral bone disorder (CKD-MBD). It is well known that the bone turnover disorder is the most common complication of CKD-MBD. Besides, CKD patients usually suffer from vascular calcification (VC), which is highly associated with mortality. Many factors regulate the VC mechanism, which include imbalances in serum calcium and phosphate, systemic inflammation, RANK/RANKL/OPG triad, aldosterone, microRNAs, osteogenic transdifferentiation, and effects of vitamins. These factors have roles in both promoting and inhibiting VC. Patients with CKD usually have bone turnover problems. Patients with high bone turnover have increase of calcium and phosphate release from the bone. By contrast, when bone turnover is low, serum calcium and phosphate levels are frequently maintained at high levels because the reservoir functions of bone decrease. Both of these conditions will increase the possibility of VC. In addition, the calcified vessel may secrete FGF23 and Wnt inhibitors such as sclerostin, DKK-1, and secreted frizzled-related protein to prevent further VC. However, all of them may fight back the inhibition of bone formation resulting in fragile bone. There are several ways to treat VC depending on the bone turnover status of the individual. The main goals of therapy are to maintain normal bone turnover and protect against VC.

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Related in: MedlinePlus

Factors related to the osteogenic transdifferentiation of vascular smooth muscle cells in chronic kidney disease (CKD). Hyperphosphatemia stimulates the secretion of FGF-23 from osteocytes in the bone, which inhibit the activity of angiotensin-converting enzyme 2 (ACE2). FGF23 blocks the conversion of angiotensin II into angiotensin (1-7). Therefore, angiotensin II will enhance the production of aldosterone. Phosphate and calcium stimulate the Na-Pi cotransporter, and aldosterone also contributes to activate the Na-Pi cotransporter, resulting in increased phosphate entrance into VSMCs. In addition, aldosterone accentuates the inflammatory status in part by TNFα. Both oxidative/inflammatory status and increased intracellular phosphate levels promote VSMCs to transdifferentiate into phenotypic osteoblast cells, which causes the ossification of the vascular wall to progress. As a whole, the calcified vessels have more prominent bone formation characteristic than bone resorption ones. In addition, osteogenic cells may secrete sclerostin (SOST) and FGF23. The secreted FGF23 from the calcified vessel may contribute further increased FGF23 serum levels.
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fig3: Factors related to the osteogenic transdifferentiation of vascular smooth muscle cells in chronic kidney disease (CKD). Hyperphosphatemia stimulates the secretion of FGF-23 from osteocytes in the bone, which inhibit the activity of angiotensin-converting enzyme 2 (ACE2). FGF23 blocks the conversion of angiotensin II into angiotensin (1-7). Therefore, angiotensin II will enhance the production of aldosterone. Phosphate and calcium stimulate the Na-Pi cotransporter, and aldosterone also contributes to activate the Na-Pi cotransporter, resulting in increased phosphate entrance into VSMCs. In addition, aldosterone accentuates the inflammatory status in part by TNFα. Both oxidative/inflammatory status and increased intracellular phosphate levels promote VSMCs to transdifferentiate into phenotypic osteoblast cells, which causes the ossification of the vascular wall to progress. As a whole, the calcified vessels have more prominent bone formation characteristic than bone resorption ones. In addition, osteogenic cells may secrete sclerostin (SOST) and FGF23. The secreted FGF23 from the calcified vessel may contribute further increased FGF23 serum levels.

Mentions: Elevated serum phosphate may stimulate FGF23 production, which in turn may inhibit the angiotensin converting enzyme (ACE) 2, resulting in increased angiotensin II (Figure 3) and aldosterone levels in CKD [129]. VSMCs express mineralocorticoid receptors and their activation by mineralocorticoids promotes VC [130, 131]. High-plasma aldosterone concentrations are related to vascular stiffening, vascular damage, and atherosclerosis [132–134]. Aldosterone could directly regulate the type III sodium-dependent phosphate transporter-phosphate transporter 1 (Pit-1) in vitro. Pit-1 is required for the subsequent TNFα/Msx2 cascade, causing chondroosteogenic transformation as well [135]. In addition, aldosterone also upregulates vascular TNFα [136]. TNFα promotes the differentiation of VSMCs into cells that are characteristic of chondroblastic/osteoblastic cells [137]. TNFα stimulates the expression of the chondroosteogenic transcription factors osterix and Cbfα1/Runx2. This step includes the transcription factors Nf-κB and Msx2 [138]. Cbfα1/Runx2 is another key factor in triggering VC [139].


Vascular calcification and renal bone disorders.

Lu KC, Wu CC, Yen JF, Liu WC - ScientificWorldJournal (2014)

Factors related to the osteogenic transdifferentiation of vascular smooth muscle cells in chronic kidney disease (CKD). Hyperphosphatemia stimulates the secretion of FGF-23 from osteocytes in the bone, which inhibit the activity of angiotensin-converting enzyme 2 (ACE2). FGF23 blocks the conversion of angiotensin II into angiotensin (1-7). Therefore, angiotensin II will enhance the production of aldosterone. Phosphate and calcium stimulate the Na-Pi cotransporter, and aldosterone also contributes to activate the Na-Pi cotransporter, resulting in increased phosphate entrance into VSMCs. In addition, aldosterone accentuates the inflammatory status in part by TNFα. Both oxidative/inflammatory status and increased intracellular phosphate levels promote VSMCs to transdifferentiate into phenotypic osteoblast cells, which causes the ossification of the vascular wall to progress. As a whole, the calcified vessels have more prominent bone formation characteristic than bone resorption ones. In addition, osteogenic cells may secrete sclerostin (SOST) and FGF23. The secreted FGF23 from the calcified vessel may contribute further increased FGF23 serum levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127293&req=5

fig3: Factors related to the osteogenic transdifferentiation of vascular smooth muscle cells in chronic kidney disease (CKD). Hyperphosphatemia stimulates the secretion of FGF-23 from osteocytes in the bone, which inhibit the activity of angiotensin-converting enzyme 2 (ACE2). FGF23 blocks the conversion of angiotensin II into angiotensin (1-7). Therefore, angiotensin II will enhance the production of aldosterone. Phosphate and calcium stimulate the Na-Pi cotransporter, and aldosterone also contributes to activate the Na-Pi cotransporter, resulting in increased phosphate entrance into VSMCs. In addition, aldosterone accentuates the inflammatory status in part by TNFα. Both oxidative/inflammatory status and increased intracellular phosphate levels promote VSMCs to transdifferentiate into phenotypic osteoblast cells, which causes the ossification of the vascular wall to progress. As a whole, the calcified vessels have more prominent bone formation characteristic than bone resorption ones. In addition, osteogenic cells may secrete sclerostin (SOST) and FGF23. The secreted FGF23 from the calcified vessel may contribute further increased FGF23 serum levels.
Mentions: Elevated serum phosphate may stimulate FGF23 production, which in turn may inhibit the angiotensin converting enzyme (ACE) 2, resulting in increased angiotensin II (Figure 3) and aldosterone levels in CKD [129]. VSMCs express mineralocorticoid receptors and their activation by mineralocorticoids promotes VC [130, 131]. High-plasma aldosterone concentrations are related to vascular stiffening, vascular damage, and atherosclerosis [132–134]. Aldosterone could directly regulate the type III sodium-dependent phosphate transporter-phosphate transporter 1 (Pit-1) in vitro. Pit-1 is required for the subsequent TNFα/Msx2 cascade, causing chondroosteogenic transformation as well [135]. In addition, aldosterone also upregulates vascular TNFα [136]. TNFα promotes the differentiation of VSMCs into cells that are characteristic of chondroblastic/osteoblastic cells [137]. TNFα stimulates the expression of the chondroosteogenic transcription factors osterix and Cbfα1/Runx2. This step includes the transcription factors Nf-κB and Msx2 [138]. Cbfα1/Runx2 is another key factor in triggering VC [139].

Bottom Line: Besides, CKD patients usually suffer from vascular calcification (VC), which is highly associated with mortality.These factors have roles in both promoting and inhibiting VC.In addition, the calcified vessel may secrete FGF23 and Wnt inhibitors such as sclerostin, DKK-1, and secreted frizzled-related protein to prevent further VC.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan.

ABSTRACT
At the early stage of chronic kidney disease (CKD), the systemic mineral metabolism and bone composition start to change. This alteration is known as chronic kidney disease-mineral bone disorder (CKD-MBD). It is well known that the bone turnover disorder is the most common complication of CKD-MBD. Besides, CKD patients usually suffer from vascular calcification (VC), which is highly associated with mortality. Many factors regulate the VC mechanism, which include imbalances in serum calcium and phosphate, systemic inflammation, RANK/RANKL/OPG triad, aldosterone, microRNAs, osteogenic transdifferentiation, and effects of vitamins. These factors have roles in both promoting and inhibiting VC. Patients with CKD usually have bone turnover problems. Patients with high bone turnover have increase of calcium and phosphate release from the bone. By contrast, when bone turnover is low, serum calcium and phosphate levels are frequently maintained at high levels because the reservoir functions of bone decrease. Both of these conditions will increase the possibility of VC. In addition, the calcified vessel may secrete FGF23 and Wnt inhibitors such as sclerostin, DKK-1, and secreted frizzled-related protein to prevent further VC. However, all of them may fight back the inhibition of bone formation resulting in fragile bone. There are several ways to treat VC depending on the bone turnover status of the individual. The main goals of therapy are to maintain normal bone turnover and protect against VC.

Show MeSH
Related in: MedlinePlus