Skeletal fracture contributes to significant morbidity throughout the human population. Furthermore, in our aging population, the increased incidence of osteoporosis is associated with skeletal injuries, such as hip fractures, resulting in considerable mortality. It is thus important to understand the mechanisms and the molecules involved in fracture repair and the response of the skeleton to mechanical stress. The importance of FGF signaling in skeletal biology is illustrated by the large number of missense mutations in the genes encoding FGF receptors (FGFRs) 1, 2 and 3 that are the etiology of many human craniosynostosis and chondrodysplasia syndromes. Furthermore, loss of function and skeletal-specific conditional loss of function mutations in mouse FGFRs 1,2 and 3 also show specific defects in skeletal development and in the structure and integrity of adult bone. The studies proposed here should provide guidance for the potential manipulation of FGF signaling to treat skeletal injury and disease. 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. Adult mice lacking FGF2 (bFGF) 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 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. In this proposal we will: 1) Test the hypothesis that Fgf9, Fgf18 and possibly Fgf2 have redundancy in expression patterns during skeletal development, repair and response to mechanical loading;2) We will characterize the skeletal phenotypes of mice lacking FGF9, FGF18 and both FGF9 and FGF18 and we will determine whether FGF2 has redundant interactions with FGF9 and FGF18;3) We will determine the mechanism by which FGF9 and FGF18 regulate vascularization of endochondral bone;4) We will test the hypothesis that in response to mechanical load, FGF signaling is required for cortical bone formation and associated increased periosteal vascularization.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 1 Study Section (DEV1)
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Winer, Karen
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Washington University
Other Basic Sciences
Schools of Medicine
Saint Louis
United States
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Ornitz, David M; Legeai-Mallet, Laurence (2017) Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 246:291-309
Karuppaiah, Kannan; Yu, Kai; Lim, Joohyun et al. (2016) FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development 143:1811-22
Öztürk, Ece; Arlov, Øystein; Aksel, Seda et al. (2016) Sulfated hydrogel matrices direct mitogenicity and maintenance of chondrocyte phenotype through activation of FGF signaling. Adv Funct Mater 26:3649-3662
Hung, Irene H; Schoenwolf, Gary C; Lewandoski, Mark et al. (2016) A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol 411:72-84
Luo, Xianmin; Fu, Yujie; Loza, Andrew J et al. (2016) Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development. Cell Rep 14:82-92
Ornitz, David M; Itoh, Nobuyuki (2015) The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol 4:215-66
Yu, Kai; Karuppaiah, Kannan; Ornitz, David M (2015) Mesenchymal fibroblast growth factor receptor signaling regulates palatal shelf elevation during secondary palate formation. Dev Dyn 244:1427-38
Ornitz, David M; Marie, Pierre J (2015) Fibroblast growth factor signaling in skeletal development and disease. Genes Dev 29:1463-86
Chen, Jianquan; Shi, Yu; Regan, Jenna et al. (2014) Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PLoS One 9:e85161
Long, Fanxin; Ornitz, David M (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5:a008334

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