Marrow adipocytes inhibit the differentiation of mesenchymal stem cells into osteoblasts via suppressing BMP-signaling

Background: reduced bone formation is associated with increased bone marrow fat in many bone-loss related diseases including aging,post-menopause,and anorexia nervosa. several lines of evidence suggested the regulation of osteogenesis and adipogenesis of the bone marrow-derived mesenchymal (skeletal) stem cells (bmscs) by paracrine mediators. this study aimed to investigate the impact of adipocytes-secreted factors on the cell proliferation and osteoblast differentiation of bmscs. methods: serum free conditioned medium (cm-adipo) was collected from stromal st2 cells-derived adipocytes. cell viability,quantitative alkaline phosphatase (alp) activity assay,alizarin red staining for matrix mineralization and osteogenic gene array expression were performed to determine the effect of cm-adipo on cell proliferation and osteoblast differentiation of primary murine bmscs (mbmscs). regulation of bmps and nf-κb signaling pathways by cm-adipo were detected by western blot analysis and gene reporter assay. results: cm-adipo showed no effect on cell viability/proliferation of primary mbmscs as compared to cm-control. on the other hand,cm-adipo significantly inhibited the commitment of mbmscs into osteoblastic cell lineage in dose-dependent manner. cm-adipo was found to dramatically inhibit the bmp2-induced osteoblast differentiation and to activate the inflammatory nf-κb signaling in mbmscs. interestingly,treatment of mbmscs with the selective inhibitor of nf-κb pathway,bay11-770682,showed to retrieve the inhibitory effect of cm-adipo on bmp2-induced osteoblast differentiation in mbmscs. conclusions: our data demonstrated that the marrow adipocytes exert paracrine inhibitory effect on the osteoblast differentiation of mbmscs by blocking bmps signaling in a mechanism mediated by adipokines-induced nf-κb pathway activation. © 2017 the author(s).