title: MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells.
abstract: Osteoblast differentiation of valve interstitial cells (VICs) is a key step in valve calcification, but the molecular mechanisms involved are not fully understood. In this study, we aimed to investigate whether microRNA (miR)-204-regulated VICs differentiation through modulation of runt-related transcription factor 2 (Runx2), a key transcription factor for osteogenesis. Our data demonstrated that miR-204 was markedly downregulated in both human calcified aortic valves and bone morphogenetic protein (BMP)-2-stimulated aortic VICs. In vitro experiments showed that miR-204 acted as a negative regulator of osteogenic differentiation by repressing Runx2 and thereby inhibiting expression of osteoblast-related genes, including alkaline phosphatase and osteocalcin, which were all induced by BMP-2. Luciferase reporter assays validated Runx2 as the direct target of miR-204. Furthermore, increased alkaline phosphatase activity and osteocalcin expression after miR-204 inhibition were abolished by small interfering RNA-mediated silencing of Runx2. Overall, these data suggested miR-204 as a possible molecular switch inhibiting osteoblastic transdifferentiation of human aortic VICs and targeting miR-204 may have therapeutic potential for human aortic valve calcification.
authors: Department of Cardiovascular Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Yongjun
authors: Y
authors: Wang
authors: Si
authors: S
authors: Chen
authors: Cheng
authors: C
authors: Deng
authors: Fei
authors: F
authors: Li
authors: Yin
authors: Y
authors: Wang
authors: Xingjian
authors: X
authors: Hu
authors: Feng
authors: F
authors: Shi
authors: Nianguo
authors: N
authors: Dong
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000008:administration & dosage* / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; C493709:RUNX2 protein, human