Skeletal morphogenesis is controlled by a network of signaling molecules that first determine the fate of undifferentiated stem cells of the mesenchymal lineage and then regulate the proliferation and differentiation of committed osteogenic cells. Among the signaling molecules which influence bone morphogenesis, fibroblast growth factors (FGF) and their cognate receptors (FGFR) have been recently shown to play a major role both in endochondral and intramembranous bone formation. Activating mutations in FGFR3 have been shown to be responsible for several genetic forms of human dwarfism, and other activating mutations in FGFR1, FGFR2 and FGFR3 have been linked to many craniosynostosis syndromes. Mouse genetic experiments have confirmed that unregulated FGF signaling causes bone malformations and suggested that FGFs may act as negative regulators of bone growth. However, the molecular mechanisms through which FGFs influence the proliferation of differentiation of osteogenic cells (e.g. chondrocytes and osteoblasts) remain to be elucidated. The goal of this research project is to study the response to FGF signaling of chondrocytes. We have shown that FGF treatment inhibits the proliferation of chondrocytes, and that this inhibition requires activation of the STAT-1 pathway. Using organ cultures of metatarsal bones rudiments of E15 murine embryos we have also shown that FGFs regulate chondrocyte proliferation and bone development and that this effect also requires STAT-1. We wish to understand the molecular mechanisms underlying the growth inhibitory response of chondrocytes to FGF signaling and how FGF signaling affects chondrocyte proliferation and differentiation. We will study 1) the signal transduction pathways activated by FGF receptors in chondrocytes with an emphasis on the mechanisms leading to activation on STAT-1, which plays an essential role in the chondrocyte response to FGF; 2) how the progress of the differentiation program which takes place during organ culture of bone rudiments from murine embryos is affected by FGF treatment or by molecules in the FGF signaling pathways; 3) the effect of modulating FGF signaling on bone morphogenesis in vivo, using transgenic and knockout mice, to verify how STAT-1 influences long bone development and chondrodysplasia.
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