During the past year, it has become apparent that members of the fibroblast growth factor (FGF) family of ligands and receptors are both required and essential for normal skeletal growth. Recent observations show that a number of inherited disorders of skeletal growth are due to point mutations in FGF receptors. It is also known that members of the FGF superfamily are expressed by bone cells, store in the bone matrix and stimulate bone formation in vivo. However, there are many important unanswered questions which need to be addressed, particularly with respect to the effects of this growth factor family on normal bone cell proliferation and differentiation, which ligands and receptors are responsible for the effects of the FGF's in normal skeletal development, and the potential for this information to be used therapeutically to stimulate bone formation. We believe the tools are now available to answer some of these important questions. We propose the following set of objective. 1. Identification of the FGF receptors and ligands which are expressed in normal bone cells during normal bone cell differentiation in vitro and in vivo. 2. Evaluation of mutant forms of FGF's for effects on bone in vitro and in vivo. Our knowledge of the regulatory mechanisms for normal bone formation is not well developed. The recent observations in these inherited disorders of skeletal development point to an important role of the FGF family of ligands receptors. The experiments we propose are designed to increase our knowledge of their precise effects on bones cells during normal bone formation and test their potential as therapies for common bone diseases.
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