Fibroblast growth factor receptor 3 (FGFR3) is a chief regulator of endochondral bone growth, as evidenced by the discovery that the most common genetic cause of dwarfism, achondroplasia, results from mutations in FGFR3. This implies that pathways downstream of FGFR3 are central to the control of skeletal growth. Our goals are to understand the signaling pathways used by FGFR3 to control cell proliferation and differentiation during skeletal growth and development. Understanding these pathways will lead to novel interventions for the control of skeletal growth and suggest approaches for promoting cartilage repair and regeneration. We hypothesize that FGFR3 inhibits cell proliferation by accelerating pathways of cell senescence and inhibits cell differentiation by repressing BMP4 expression. These hypotheses are a direct consequence of our preliminary data showing that FGFR3 reduces the number of chondrocytes in S-phase and slows the rate of chondrocyte and osteoprogenitor cell differentiation. Intriguingly, FGFR3 represses the expression of bone morphogenetic protein 4 (BMP4) both in chondrocytes and perichondrial osteoprogenitor cells, suggesting that FGFR3 may synchronize bone growth in the perichondrium with the growth of the epiphyseal growth plate by modulating BMP4 expression. Despite this knowledge, much remains to be learned about how FGFR3 inhibits skeletal growth. Specifically, what are the pathways used by FGFR3 to inhibit cell proliferation and what are the mediators downstream of FGFR3 that inhibit perichondrial and chondrocyte differentiation? Without understanding these fundamental questions there is little hope of designing interventional treatments for dwarfing conditions such as achondroplasia. We will address these questions and test our hypotheses by pursuing the following specific aims: 1) Investigate how FGFR3 inhibits chondrocyte proliferation by testing the hypothesis that FGFR3 accelerates cell cycle senescence; 2a) Determine how BMP4 acts as a mediator of FGFR3 signaling by targeting the expression of BMP4 to cartilage of transgenic mice and 2b) Using a cre-lox system to express BMP4 in transgenic mice, investigate the separate and combined roles of BMP4 in cartilage and the perichondrium. These studies will utilize unique reagents, including FGFR3 transgenic mice, created during our preliminary studies. Using these reagents we can directly test what effects of FGFR3 are consequences of altered BMP4 expression. These studies will fundamentally advance our understanding of the communication of the growth plate and the perichondrium and unravel novel growth regulatory pathways of FGFR3 and BMP4. We anticipate these studies will suggest new ways to control skeletal growth and to promote cartilage repair and regeneration.
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