title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind., USA.
authors.forename: Neal X
authors.initials: NX
authors.lastname: Chen
authors.forename: Kalisha D
authors.initials: KD
authors.lastname: O'Neill
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Newman
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Moe
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016723:Bone Remodeling; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D010006:Osteoblasts / Q000502:physiology*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000235:genetics; D010281:Parathyroid Hormone / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; D010281:Parathyroid Hormone; D012333:RNA, Messenger; C493717:Runx2 protein, rat; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000469:Alkaline Phosphatase