The Role of Cytoskeleton Signaling in Controlling the Commitment of Progenitors to Adipose Lineage versus Osteoblast Lineage

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 649-677-Adipocyte Biology
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-655
Hejiao Bian* and Stephen R Farmer
Boston University, Boston, MA
Arising from common progenitors in the bone marrow, adipogenesis and osteogenesis are closely associated yet mutually exclusive during mesenchymal stem cell (MSC) development. Various human diseases have been shown to develop once the delicate balance between adipogenesis and osteogenesis is disrupted. For example, in age-related osteoporosis and secondary osteoporosis as seen in type 2 diabetic patients treated with thiazolidinediones (TZDs), the loss of bone mass was often found to be accompanied with significantly increased accumulation of adipocytes in the bone marrow.  Investigating the underlying molecular mechanisms of the osteo-adipogenic switch under these conditions may lead to the development of clinical preventative strategies and therapies for osteoporosis patients.

While changes in cell morphology and cytoskeletal integrity can alter pre-committed mesenchymal stem cell differentiation of certain lineages, previous studies have shown that the morphological changes can also affect the early commitment of pluripotent mesenchymal stem cells via modulation of RhoA activity. The RhoA pathway regulates actin polymerization dynamics through various effectors including Rho-associated kinases (ROCKs) and Actin Binding Proteins (ABPs) to promote the incorporation of Globular-actin (G-actin) into Filament-actin (F-actin). In doing so, Myocardin-related transcription factors (MRTFs) bound with G-actin are released for nuclear import to co-activate Serum Response Factor (SRF) cytoskeletal target genes. Exactly how the RhoA-actin-MRTF-SRF circuit is involved in the regulation of early commitment of mesenchymal stem cells is still poorly understood.

In this study, the role of the MRTFA/SRF-actin circuit in the commitment of mesenchymal stem cells into adipogenic versus osteogenic lineages has been investigated. Preliminary results showed that MRTFA and SRF inhibits adipogenesis and enhances osteogenesis in murine pluripotent MSCs, whereas dominant-negative MRTFA and SRF had the opposite effects. Bone marrow stem cells isolated from global MRTFA knockout mice showed increased adipogenesis and compromised osteogenesis when compared to WT littermates. The SRF inhibitor, CCG1423, mimicked the effects of knocking out MRTFA in WT mouse bone marrow stem cells by inhibiting osteogenesis and promoting adipogenesis. MRTFA and SRF appear to be crucial regulators of the balance between adipogenic and osteogenic differentiation of the mesenchymal stem cells.

Nothing to Disclose: HB, SRF

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Sources of Research Support: NIH Grant NIH-DK-51586