MECHANISMS OF FGF RESPONSES IN OSTEOGENIC CELLS

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DESCRIPTION (provided by applicant): The family of fibroblast growth factors (FGFs) and cognate receptors plays an important role in a large number of developmental processes, including bone and skeletal development. Activating mutations in FGF receptors (FGFRs) cause a number of human bone morphogenetic disorders, including dwarfism and craniosynostosis (premature closure of cranial sutures) syndromes, by affecting the proliferation and differentiation of the two major cell types responsible for bone formation, chondrocytes and osteoblasts. The main focus of this project is the investigation of the mechanisms that determine the response to FGF of osteoblasts. While in most cell types FGFs induce proliferation and protect from apoptosis, osteoblasts display a stage-specific response. Immature osteoblasts respond with increased proliferation, while differentiating osteoblasts instead lose the proliferative response and undergo extensive apoptosis. Exposure to constitutive FGF signaling inhibits their ability to differentiate. Understanding the mechanisms underlying these responses will further our understanding of the pathological effects of excessive FGF signaling in calvarial osteoblasts, including craniosynostosis and skull malformations, as well as the role of FGFs in the physiological control of osteoblast growth and differentiation. We have obtained results indicating one of the major effects of FGFs on osteoblasts is inhibition of the Wnt signaling pathway. Wnt signaling is required for osteoblast differentiation and function, and thus this phenomenon could play an important role in the impairment of differentiation induced by FGF. We have also observed a striking induction of the expression of Sox2, a member of the HMG domain family of transcription factors, and shown that constitutive expression of Sox2 can inhibit osteoblast differentiation and cause Wnt signaling downregulation. The goals of this project are: 1) to further study the mechanisms which determine the biological response of osteoblasts to FGF signaling, investigate the role that Sox2 and Wnt signaling play in the response of osteoblasts to FGF, and determine how Sox2 modulates Wnt signaling; 2) to investigate the mechanisms by which FGF signaling induces Sox2 expression in osteoblasts, that appears to be a cell type-specific response; 3) verify in vivo the observations and hypotheses derived from in vitro studies using a murine model of FGF-induced craniosynostosis and mice with impaired Sox2 expression in the osteoblastic lineage.