Endochondral ossification is a major process in skeletal development and repair, during which mesenchymal progenitors undergo growth and differentiation into mature chondrocytes prior to bone formation. Several signaling pathways contribute to precise regulation of the onset and progression of chondrocyte maturation during endochondral ossification through transcriptional regulation. The early molecular mechanisms that mediate and promote endochondral ossification during bone repair are still unknown, and for the most part, not well established. The Runt homology of transcription factors Runx 1, 2 and 3 are key regulators of organogenesis and skeletal formation. We have compelling preliminary data to support our central hypothesis that the hematopoietic-related transcription factor Runx1/AML1/Cbfa2 is necessary for mesenchymal stem cell commitment towards chondrogenesis and mediates the early stages of chondrocyte maturation. We will assess the expression and regulation of Runx1 in vivo and in vitro in ? comparison to the already established bone and cartilage-related factor Runx2/AML3/Cbfa1 (Specific Aim 1). We will then determine the function of Runx1 during chondrogenesis and chondrocyte maturation in vitro using gain and loss of function approaches (Specific Aim 2). Its requirement for bone repair will be determined through fracture healing experiments, and Its role in mediating endochondral ossification in vivo will also be assessed using trangenic mouse models (Specific Aim 3). Our preliminary data show for the first time that Runx1/AML1/Cbfa2 is a central regulator of endochondral ossification and cartilage formation at multiple levels. Furthermore, its function is not redundant but complementary to Runx2/AML3/Cbfa1 which mediates the late stages of chondrocyte hypertrophy and mineralization. Completion of our experimental aims will provide crucial information regarding skeletal formation and repair as well as novel molecular candidates for the treatment of bone and cartilage diseases. ? ?
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