Endochondral ossification is a complex, multistep process during which immature chondrocytes first proliferate, then become postmitotic, undergo hypertrophy, and are replaced by bone cells. The initial step of chondrocyte proliferation is critical since it sets the overall maturation process in motion, is a determinant of growth rates and, when abnormal, can lead to skeletal defects. Despite its obvious importance, relatively little is known about its regulation (e.g., what triggers the onset, and end of chondrocyte proliferation?; which factors regulate it and how do they act?). Studies from the applicant, and other laboratories have now shown that fibroblast growth factors (FGFs) and their cell surface receptors (FGF-Rs) and co-receptors (heparin sulfate -rich syndecans) have critical roles in chondrocyte proliferation. The applicant group and others have shown that proliferating chondrocytes in the growth plate express FGF-2 and syndecan-3, that chronic treatment with FGF-2 in vitro, or constitutive FGF-2 expression in transgenic mice stimulate chondrocyte proliferation, and that the mitotic response of chondrocytes to FGF-2 is mediated by syndecan-3. On the other hand, gene expression, gene ablation and genetic studies have indicated that proliferating and postmitotic pre-hypertrophic chondrocytes in the growth plate express FGF-R3, and that this receptor plays a negative role and inhibits proliferation. Thus, it appears that chondrocyte proliferation is regulated by both stimulatory and inhibitory mechanisms. The applicant proposes to test his hypothesis that FGF-2 and syndecan-3 interact with an FGF-R and stimulate proliferation, whereas FGF-R3 is part of counterbalancing negative mechanisms which limit proliferation. The group will attempt to determine: (a) the role of different syndecans and FGFs in chondrocyte proliferation; (b) the expression patterns and roles of FGF-R family members; (c) the interactions between syndecans and FGF-Rs; (d) the role of syndecan core protein in co-receptor function; and (e) the effects of deregulated syndecan expression in skeletogenesis in vivo. It is suggested that these results will provide much needed information on how chondrocyte proliferation is spatially restricted during skeletogenesis, and may suggest ways to restore normal chondrocyte behavior in congenital and acquired conditions of endochondral bone formation.
| Pacifici, Maurizio; Shimo, Tsuyoshi; Gentili, Chiara et al. (2005) Syndecan-3: a cell-surface heparan sulfate proteoglycan important for chondrocyte proliferation and function during limb skeletogenesis. J Bone Miner Metab 23:191-9 |
| Shimo, Tsuyoshi; Koyama, Eiki; Sugito, Hiroki et al. (2005) Retinoid signaling regulates CTGF expression in hypertrophic chondrocytes with differential involvement of MAP kinases. J Bone Miner Res 20:867-77 |
| Shimo, Tsuyoshi; Gentili, Chiara; Iwamoto, Masahiro et al. (2004) Indian hedgehog and syndecans-3 coregulate chondrocyte proliferation and function during chick limb skeletogenesis. Dev Dyn 229:607-17 |
| Yin, M; Pacifici, M (2001) Vascular regression is required for mesenchymal condensation and chondrogenesis in the developing limb. Dev Dyn 222:522-33 |
| Dangelo, M; Sarment, D P; Billings, P C et al. (2001) Activation of transforming growth factor beta in chondrocytes undergoing endochondral ossification. J Bone Miner Res 16:2339-47 |
