title: Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification.
abstract: BACKGROUND
  Vascular calcification is a hallmark of atherosclerosis, a major cause of morbidity and mortality in the United States. We have previously reported that the osteogenic transcription factor Runx2 is an essential and sufficient regulator of calcification of vascular smooth muscle cells (VSMC) in vitro.
  
  
  OBJECTIVE
  To determine the contribution of osteogenic differentiation of VSMC to the pathogenesis of vascular calcification and the function of VSMC-derived Runx2 in regulating calcification in vivo.
  
  
  RESULTS
  SMC-specific Runx2-deficient mice, generated by breeding SM22α-Cre mice with the Runx2 exon 8 floxed mice, exhibited normal aortic gross anatomy and expression levels of SMC-specific marker genes. Runx2 deficiency did not affect basal SMC markers, but inhibited oxidative stress-reduced expression of SMC markers. High-fat-diet-induced vascular calcification in vivo was markedly inhibited in the Runx2-deficient mice in comparison with their control littermates. Runx2 deficiency inhibited the expression of receptor activator of nuclear factor κB ligand, which was accompanied by decreased macrophage infiltration and formation of osteoclast-like cells in the calcified lesions. Coculture of VSMC with bone marrow-derived macrophages demonstrated that the Runx2-deficient VSMC failed to promote differentiation of macrophages into osteoclast-like cells.
  
  
  CONCLUSIONS
  These data have determined the importance of osteogenic differentiation of VSMC in the pathogenesis of vascular calcification in mice and defined the functional role of SMC-derived Runx2 in regulating vascular calcification and promoting infiltration of macrophages into the calcified lesion to form osteoclast-like cells. Our studies suggest that the development of vascular calcification is coupled with the formation of osteoclast-like cells, paralleling the bone remodeling process.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Yong
authors: Y
authors: Sun
authors: Chang Hyun
authors: CH
authors: Byon
authors: Kaiyu
authors: K
authors: Yuan
authors: Jianfeng
authors: J
authors: Chen
authors: Xia
authors: X
authors: Mao
authors: Jack M
authors: JM
authors: Heath
authors: Amjad
authors: A
authors: Javed
authors: Kui
authors: K
authors: Zhang
authors: Peter G
authors: PG
authors: Anderson
authors: Yabing
authors: Y
authors: Chen
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology* / Q000503:physiopathology; D016723:Bone Remodeling / Q000502:physiology; D002114:Calcinosis / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency / Q000235:genetics*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D016296:Mutagenesis / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D007527:Isoenzymes; D053245:RANK Ligand; C493716:Runx2 protein, mouse; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase