Skeletal morphogenesis is controlled by a network of signaling molecules that first determine the fate of undifferentiated stem cells of the mesenchymal lineage and then regulate the proliferation and differentiation of committed osteogenic cells. Among the signaling molecules which influence bone morphogenesis, fibroblast growth factors (FGF) and their cognate receptors (FGFR) have been recently shown to play a major role both in endochondral and intramembranous bone formation. Activating mutations in FGFR3 have been shown to be responsible for several genetic forms of human dwarfism, and other activating mutations in FGFR1, FGFR2 and FGFR3 have been linked to many craniosynostosis syndromes. Mouse genetic experiments have confirmed that unregulated FGF signaling causes bone malformations and suggested that FGFs may act as negative regulators of bone growth. However, the molecular mechanisms through which FGFs influence the proliferation of differentiation of osteogenic cells (e.g. chondrocytes and osteoblasts) remain to be elucidated. The goal of this research project is to study the response to FGF signaling of chondrocytes. We have shown that FGF treatment inhibits the proliferation of chondrocytes, and that this inhibition requires activation of the STAT-1 pathway. Using organ cultures of metatarsal bones rudiments of E15 murine embryos we have also shown that FGFs regulate chondrocyte proliferation and bone development and that this effect also requires STAT-1. We wish to understand the molecular mechanisms underlying the growth inhibitory response of chondrocytes to FGF signaling and how FGF signaling affects chondrocyte proliferation and differentiation. We will study 1) the signal transduction pathways activated by FGF receptors in chondrocytes with an emphasis on the mechanisms leading to activation on STAT-1, which plays an essential role in the chondrocyte response to FGF; 2) how the progress of the differentiation program which takes place during organ culture of bone rudiments from murine embryos is affected by FGF treatment or by molecules in the FGF signaling pathways; 3) the effect of modulating FGF signaling on bone morphogenesis in vivo, using transgenic and knockout mice, to verify how STAT-1 influences long bone development and chondrodysplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013745-03
Application #
6626945
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Small, Rochelle K
Project Start
2001-02-01
Project End
2005-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2003
Total Cost
$406,463
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kolupaeva, Victoria; Daempfling, Lea; Basilico, Claudio (2013) The B55* regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes. Mol Cell Biol 33:2865-78
Basu-Roy, Upal; Basilico, Claudio; Mansukhani, Alka (2013) Perspectives on cancer stem cells in osteosarcoma. Cancer Lett 338:158-67
Kolupaeva, Victoria; Basilico, Claudio (2012) Overexpression of cyclin E/CDK2 complexes overcomes FGF-induced cell cycle arrest in the presence of hypophosphorylated Rb proteins. Cell Cycle 11:2557-66
Basu-Roy, U; Seo, E; Ramanathapuram, L et al. (2012) Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas. Oncogene 31:2270-82
Tran, Tri; Kolupaeva, Victoria; Basilico, Claudio (2010) FGF inhibits the activity of the cyclin B1/CDK1 kinase to induce a transient G?arrest in RCS chondrocytes. Cell Cycle 9:4379-86
Kolupaeva, Victoria; Laplantine, Emmanuel; Basilico, Claudio (2008) PP2A-mediated dephosphorylation of p107 plays a critical role in chondrocyte cell cycle arrest by FGF. PLoS One 3:e3447
Yaragatti, Mahesh; Basilico, Claudio; Dailey, Lisa (2008) Identification of active transcriptional regulatory modules by the functional assay of DNA from nucleosome-free regions. Genome Res 18:930-8
Priore, Riccardo; Dailey, Lisa; Basilico, Claudio (2006) Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes. J Cell Physiol 207:800-8
Mansukhani, Alka; Ambrosetti, Davide; Holmes, Greg et al. (2005) Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation. J Cell Biol 168:1065-76
Olsen, Shaun K; Ibrahimi, Omar A; Raucci, Angela et al. (2004) Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc Natl Acad Sci U S A 101:935-40

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