The role of myocardin related transcription factor A in controlling the commitment of progenitors to adipose lineage versus osteoblastic lineage
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The differentiation of osteoblasts and bone marrow adipocytes are closely associated yet mutually exclusive processes that are essential for maintaining bone homeostasis. Various diseases have been shown to develop once the delicate balance between adipogenesis and osteoblastogenesis is disrupted. Investigating the underlying molecular mechanisms of the osteoblasto-adipogenic switch under osteoporotic conditions will facilitate our understanding of the pathogenesis of osteoporosis and may eventually lead to the development of clinical therapeutic approaches for this life-threatening disease. While changes in cell morphology and cytoskeletal integrity can alter pre-committed mesenchymal stem cell (MSC) differentiation of certain lineages, previous studies have shown that cellular morphological changes can affect the early commitment of pluripotent MSCs via modulation of Ras homolog gene family, member A (RhoA) activity. The RhoA pathway regulates actin polymerization to promote the incorporation of globular-actin (G-actin) into filamentous-actin (F-actin). Actin polymerization releases G-actin bound myocardin-related transcription factors (MRTFs), which translocate to the nucleus and co-activate serum response factor (SRF) target gene expression. Exactly how the RhoA-actin-MRTF-SRF circuit is involved in the regulation of early commitment of MSCs remains poorly understood. Here we show that global MRTFA knockout mice (MRTFA KO) exhibited lower body weight, shorter femur and tibia lengths, and decreased trabecular bone volume. Furthermore, bone marrow MSCs isolated from MRTFA KO mice showed increased adipogenesis and brown fat gene expression as well as compromised osteoblastogenic differentiation as compared to WT controls. Treatment of WT bone marrow MSCs with the SRF inhibitor, CCG1423, mimicked these effects in that the compound inhibited osteoblastogenesis and promoted adipogenesis. Over-expression of MRTFA or SRF inhibited adipogenesis and enhanced osteoblastogenesis in C3H/10T1/2 cell lines, whereas over-expression of dominant-negative MRTFA or SRF variants had the opposite effects. In conclusion, our study identified MRTFA as a crucial regulator of skeletal homeostasis via regulating the balance between adipogenic and osteoblastogenic differentiation of the MSCs. Furthering our understanding of how the RhoA-actin-MRTFA-SRF circuit is involved in regulating the fate commitment of MSCs may ultimately lead to novel therapeutic strategies for treating osteoporosis and obesity.