Control of the SOST bone enhancer by PTH using MEF2 transcription factors.

摘要: Expression of the osteocyte-derived bone formation inhibitor sclerostin in adult requires a distant enhancer. We show that MEF2 transcription factors control this enhancer and mediate inhibition expression by PTH. Introduction: Sclerostin encoded SOST gene is key regulator formation. Lack cause for progressive overgrowth disorders sclerosteosis Van Buchem disease. have previously identified within 52-kb disease deletion downstream essential its bone. Furthermore, we others reported suppressed PTH. The aim study was to identify involved activity mediating PTH responsiveness. Materials Methods: Regulation promoter studied luciferase reporter assays. Transcription factor binding sites were mapped footprint analysis functional mutation analyses using transient transfections osteoblast-like UMR-106 cells exhibit endogenous expression. Specific predicted sequence shown gel retardation assays antibody-induced supershifts. myocyte 2 (MEF2) detected situ hybridization, quantitative RT-PCR (qPCR), immunohistochemistry. role MEF2s assessed siRNA-mediated RNA knockdown. Results: completely transcriptional but did not affect promoter. A response element It activation, bound factors, mediated responsiveness. qPCR, co-localized osteocytes. Enhancer stimulated MEF2C overexpression inhibited co-expression dominant negative mutant. Finally, knockdown MEF2A, C, D cells. Conclusions: These data strongly suggest osteocytes controlling Hence, are implicated regulation mass.