David M. Ornitz
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA
Abstract. Both gain-of-function and loss-of-function mutations in fibroblast growth factor receptor 3 (Fgfr3) have revealed unique roles for this receptor during skeletal development. Loss-of-function alleles of Fgfr3 lead to an increase in the size of the hypertrophic zone, delayed closure of the growth plate and the subsequent overgrowth of long bones. Gain-of-function mutations in Fgfr3 have been genetically linked to autosomal dominant dwarfing chondrodysplasia syndromes where both the size and architecture of the epiphyseal growth plate are altered. Analysis of these phenotypes and the biochemical consequences of the mutations in FGFR3 demonstrate that FGFR3-mediated signalling is an essential negative regulator of endochondral ossification.
2001 The molecular basis of skeletogenesis. Wiley, Chichester (Novartis Foundation Symposium 232)p63-80
Skeletal growth is regulated by the process of endochondral ossification, a developmental program that occurs at the ends of growing long bones and in vertebrae. During endochrondral ossification, chondrocytes differentiate through a series of well-defined morphological zones within the epiphyseal growth plate. The proliferative zone provides a renewable source of chondrocytes for longitudinal bone growth. After exiting the cell cycle maturing chondrocytes secrete a specialized extracellular matrix that includes chondroitin-sulfate proteoglycans and type II collagen. Encapsulated in this matrix, the chondrocytes undergo hypertrophy and subsequently express type X collagen and alkaline phosphatase. Hypertrophic chondrocytes undergo an apoptotic death as their surrounding matrix is mineralized and replaced by trabecular bone (Caplan & Pechak 1987).
FGF receptors (Fgfrs) 1 and 3 are both expressed in the epiphyseal growth plate. Fgfr3 is expressed in proliferating chondrocytes, whereas Fgfrl is expressed in hypertrophic chondrocytes (Peters et al 1993, Deng et al 1996). Fgfr3 is also expressed in the cartilage of the developing embryo, prior to formation of ossification centres. This expression pattern suggests a direct role for FGFR3 in regulating chondrocyte proliferation and possibly differentiation (Peters et al 1993, Delezoide et al 1998, Naski et al 1998). In contrast, Fgfrl is prominently expressed in hypertrophic chondrocytes (Peters et al 1992, Delezoide et al 1998) suggesting a role for Fgfrl in maintaining the hypertrophic phenotype of these cells (cell survival), in regulating the production of unique extracellular matrix products of hypertrophic chondrocytes or in signalling their eventual apoptotic death.
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