Skeletal biology projects:

Many of the human craniosynostosis and chondrodysplasia syndromes are caused by missense mutations in the genes encoding FGF receptors (FGFRs) 1, 2 and 3. Loss of function and skeletal-specific conditional loss of function mutations in mouse FGFRs 1-3 also show specific defects in skeletal development and in the structure and integrity of adult bone. These genetic diseases establish the essential role for FGF signaling pathways in skeletal development and physiology. In contrast to our increasing understanding of the function of FGFRs in skelatogenesis, there is little information on the FGF ligands that regulate skeletal development, growth, remodeling, vasculogenesis and repair.

Mice lacking FGF2 have a mild decrease in bone mineral density but no morphological defects in their skeleton. Mice lacking FGF18 die at birth and show moderate skeletal dismorphology. These mice also have a delayed formation of ossification centers, a phenotype not seen in mice lacking FGFRs 1, 2 or 3 in osteoblasts or chondrocytes. Recently, we have also identified a skeletal phenotype in mice lacking FGF9. These data suggest that FGF18 (and potentially FGF9) signals to both skeletal cells (chondrocytes and osteoblasts) to regulate early skeletal development and to non-skeletal mesenchymal cells to regulate peri-skeletal vasculogenesis and vascular invasion of the developing growth plate.

Ogoing projects are examining whether Fgf9, Fgf18 and Fgf2 have redundancy in expression patterns during skeletal development, repair and response to mechanical load. We will then examine the contribution of FGF signaling to the normal skeletal response to mechanical load or injury using mutants and conditional knockouts of FGF receptors.

Related projects are examining limb bud, cranial suture and palate development.

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