Low Bone Turnover in Chronic Kidney Disease Is Associated with Decreased VEGF-A Expression and Osteoblast Differentiation.

Abstract

BACKGROUND:

Low turnover bone (low bone formation rates (BFRs)) with decreased osteoblast number is common in patients with chronic kidney disease (CKD) and attributed to 'over-suppression' of the parathyroid hormone (PTH) despite supra-physiologic levels. An alternative hypothesis is abnormal osteoblast differentiation, resulting in low BFRs due to reduced VEGF-A.

METHODS:

We analyzed the expression of VEGF-A and mesenchymal stem cell (MSC) differentiation factors in freshly isolated bone marrow (BM) cells, and in BM cell-derived MSC in rats with different levels of BFRs and PTH (modulated by calcium and zoledronic acid). The regulators of VEGF in MSC were also determined.

RESULTS:

VEGF-A expression was reduced in the BM cells from CKD vs. normal animals (p < 0.02). In BM-derived MSC from CKD, there were decreased osteoblast transcription factors and mineralization. In CKD animals, the BM VEGF-A expression was positively correlated with BFR (r = 0.80, p < 0.001). Reducing BFRs in CKD animals led to reductions in VEGF-A expression and osteoblast transcription factors regardless of the PTH level. We therefore examined other regulators of VEGF-A and found decreased expression of hypoxia-inducible factor-1α and the master transcription factor of antioxidants nuclear factor (erythroid-derived 2)-like 2 in CKD animals with low PTH.

CONCLUSION:

Low BFRs in CKD are associated with a basal decrease in VEGF-A expression in BM that may be driven by altered hypoxia and oxidative stress.

• Authors: Neal X Chen, Kalisha D O'Neill, Matthew R Allen, Christopher L Newman, Sharon M Moe
• Journal: American journal of nephrology (Am J Nephrol) Vol. 41 Issue 6 Pg. 464-73 ( 2015) ISSN: 1421-9670 [Electronic] Switzerland
• PMID: 26228644 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Core Binding Factor Alpha 1 Subunit
• Hypoxia-Inducible Factor 1, alpha Subunit
• PPAR gamma
• Parathyroid Hormone
• RNA, Messenger
• Runx2 protein, rat
• Transcription Factors
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (metabolism)
• Animals
• Bone Marrow Cells (metabolism)
• Bone Remodeling
• Calcification, Physiologic
• Cell Differentiation
• Cells, Cultured
• Core Binding Factor Alpha 1 Subunit (genetics)
• Gene Expression
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Mesenchymal Stem Cells (metabolism, physiology)
• Osteoblasts (physiology)
• Oxidative Stress
• PPAR gamma (genetics)
• Parathyroid Hormone (blood)
• RNA, Messenger (metabolism)
• Rats
• Renal Insufficiency, Chronic (genetics, metabolism, physiopathology)
• Transcription Factors (genetics)
• Vascular Endothelial Growth Factor A (genetics, metabolism)