Investigator?s Abstract): Mesenchymal stromal cells undergo adipogenic and osteoblastic differentiation as a result of cell-intrinsic transcription factor programs. These differentiation programs can be regulated by TGF-beta and the TGF-beta regulated BMPs, but the underlying mechanisms are unknown. The cell surface receptors and receptors are transmembrane serine-threonine kinases, which activate the intracellular signaling effectors, Smad1, 5 and 8. These Smads then translocate into the nucleus where they regulate transcription of BMP-responsive genes. Our research is aimed at understanding the roles of the BMP receptors and Smads in the decision of a mesenchymal cell to undergo adipogenic or osteoblastic differentiation, and to progress differentiation along these lines. As a model system, we will use 3T3-F442A pre-adipocytes, which can differentiate into fat cells in vitro, and in vivo can be induced by BMPs to differentiate into osteoblasts.
Aim 1 will describe the changes in BMP receptors and Smads during adipogenic and osteoblastic differentiation and correlate these with progression of the differentiation programs. We will then define the roles of the BMP receptors and BMP Smads in adipogenic and osteoblastic differentiation in vitro (Aim 2) and in vivo (Aim 3) by enhancing or interfering with the function of individual BMP receptors or Smads. Finally, we will characterize the mechanisms of functional crosstalk between BMP Smads and the adipogenic and osteoblastic transcription factors that regulate differentiation (Aim 4).
