Myostatin (GDF-8) signaling in progenitor cells and applications to bone repair

Myostatin is a member of the TGF-Β superfamily of growth and differentiation factors and is widely recognized as a potent regulator of skeletal muscle mass and regeneration. It has, however, recently been shown that myostatin is expressed in tissues aside from muscle including fat and tendon. In addition, studies monitoring gene expression in the fracture callus following injury have shown that myostatin is highly expressed in the early phases of fracture healing. Furthermore, other research has demonstrated that mice lacking myostatin show increased bone density and a marked increase in fracture callus size following fibula osteotomy. Yet, the basic mechanisms by which myostatin may impact bone healing after injury has not been fully elucidated. Our in vitro studies using 3D aggregate culture to induce chondrogenic differentiation of bone marrow derived stromal cells (BMSCs) reveal that myostatin suppresses the proliferation and chondrogenic differentiation of BMSCs by altering the expression of Sox-9 and various Wnt-related factors. These in vitro studies suggest that myostatin may directly impair bone regeneration, a hypothesis that is also supported by our recent finding that exogenous myostatin reduces fracture callus bone volume. Together, the data suggest that myostatin may represent a novel therapeutic target for management of orthopedic trauma where both bone and muscle are damaged and, furthermore, that myostatin inhibitors may enhance fracture healing and improve recovery following musculoskeletal injury.