title: Vascular calcification in chronic kidney disease is induced by bone morphogenetic protein-2 via a mechanism involving the Wnt/β-catenin pathway.
abstract: BACKGROUND
  Vascular calcification (VC), in which vascular smooth muscle cells (VSMCs) undergo a phenotypic transformation into osteoblast-like cells, is one of the emergent risk factors for the accelerated atherosclerosis process characteristic of chronic kidney disease (CKD). Phosphate is an important regulator of VC.
  
  
  METHODS
  The expression of different smooth muscle cell or osteogenesis markers in response to high concentrations of phosphate or exogenous bone morphogenetic protein 2 (BMP-2) was examined by qRT-PCR and western blotting in rat VSMCs. Osteocalcin secretion was measured by radioimmunoassay. Differentiation and calcification of VSMCs were examined by alkaline phosphatase (ALP) activity assay and Alizarin staining. Short hairpin RNA-mediated silencing of β-catenin was performed to examine the involvement of Wnt/β-catenin signaling in VSMC calcification and osteoblastic differentiation induced by high phosphate or BMP-2. Apoptosis was determined by TUNEL assay and immunofluorescence imaging.
  
  
  RESULTS
  BMP-2 serum levels were significantly higher in CKD patients than in controls. High phosphate concentrations and BMP-2 induced VSMC apoptosis and upregulated the expression of β-catenin, Msx2, Runx2 and the phosphate cotransporter Pit1, whereas a BMP-2 neutralization antibody reversed these effects. Knockdown of β-catenin abolished the effect of high phosphate and BMP-2 on VSMC apoptosis and calcification.
  
  
  CONCLUSIONS
  BMP-2 plays a crucial role in calcium deposition in VSMCs and VC in CKD patients via a mechanism involving the Wnt/β-catenin pathway.
authors.affiliation: Department of Nephrology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Rong
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiucai
authors.initials: X
authors.lastname: Jin
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Zhu
authors.forename: Weijie
authors.initials: W
authors.lastname: Yuan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D017209:Apoptosis / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002114:Calcinosis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000254:growth & development / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D057134:Antibodies, Neutralizing; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D051176:beta Catenin