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.

Related Publications:

Colvin, J.S., Bohne, B.A., Harding, G.W., McEwen, D.G., and Ornitz, D.M. (1996). Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12, 390-397.
Naski, M.C., Colvin, J.S., Coffin, J.D., and Ornitz, D.M. (1998). Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125, 4977-4988.
Naski, M.C., and Ornitz, D.M. (1998). FGF signaling in skeletal development. Front Biosci 3, D781-794.
Ornitz, D.M. (2001). Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3. Novartis Found Symp 232, 63-76; discussion 76-80, 272-282.
Wang, Q., Green, R.P., Zhao, G., and Ornitz, D.M. (2001). Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development 128, 3867-3876.
Liu, Z., Xu, J., Colvin, J.S., and Ornitz, D.M. (2002). Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 16, 859-869.
Ornitz, D.M., and Marie, P.J. (2002). FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16, 1446-1465.
Yu, K., Xu, J., Liu, Z., Sosic, D., Shao, J., Olson, E.N., Towler, D.A., and Ornitz, D.M. (2003). Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development 130, 3063-3074.
Ornitz, D.M. (2005). FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16, 205-213.
Jacob, A.L., Smith, C., Partanen, J., and Ornitz, D.M. (2006). Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev Biol 296, 315-328.
Perlyn, C.A., Morriss-Kay, G., Darvann, T., Tenenbaum, M., and Ornitz, D.M. (2006). A model for the pharmacological treatment of crouzon syndrome. Neurosurgery 59, 210-215; discussion 210-215.
Hung, I.H., Yu, K., Lavine, K.J., and Ornitz, D.M. (2007). FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 307, 300-313.
Yu, K., and Ornitz, D.M. (2008). FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development 135, 483-491.