FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway

Abstract

Several genetic forms of human dwarfism have been linked to activating mutations in FGF receptor 3, indicating that FGF signaling has a critical role in chondrocyte maturation and skeletal development. However, the mechanisms through which FGFs affect chondrocyte proliferation and differentiation remain poorly understood. We show here that activation of FGF signaling inhibits chondrocyte proliferation both in a rat chondrosarcoma (RCS) cell line and in primary murine chondrocytes. FGF treatment of RCS cells induces phosphorylation of STAT-1, its translocation to the nucleus, and an increase in the expression of the cell-cycle inhibitor p21WAF1/CIP1. We have used primary chondrocytes from STAT-1 knock-out mice to provide genetic evidence that STAT-1 function is required for the FGF mediated growth inhibition. Furthermore, FGF treatment of metatarsal rudiments from wild-type and STAT-1 −/− murine embryos produces a drastic impairment of chondrocyte proliferation and bone development in wildtype, but not in STAT-1 −/− rudiments. We propose that STAT-1 mediated down regulation of chondrocyte proliferation by FGF signaling is an homeostatic mechanism which ensures harmonious bone development and morphogenesis.

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

“…Bones formed via either endochondral or intramembranous ossification in Stat1 Ϫ/Ϫ mice have an increase in mass and mineral density due to a disruption in the proliferation and differentiation properties of both osteoblasts and osteoclasts (Kim et al, 2003;Xiao et al, 2004), and FGFs have an anti-proliferative effect on chondrocytes that is disrupted by loss of Stat1 (Sahni et al, 1999(Sahni et al, , 2001.…”

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…It has been suggested that hyperactivation of Stat1 might be involved in the growth impairment observed in genetic forms of dwar®sm involving activated mutations in FGF receptor (Su et al, 1997). Primary chondrocytes derived from Stat1-de®cient embryos were found to be defective in FGF-mediated growth inhibition, even though normal levels of FGF receptors were expressed (Sahni et al, 1999). Furthermore, organ cultures of bone rudiments from mouse embryos showed that FGF treatment produces a drastic impairment of chrondrocyte proliferation and bone development in wild-type but not in Stat17/7 bone cultures.…”

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells

“…Missense mutations in the transmembrane region of FGFR3 result in constitutive activation and the autosomal dominant heritable disorders of skeletal development such as thanatophoric dwarfism, achondroplasia and Crouzon syndrome (Tavormina et al, 1995;Naski et al, 1996;Bonaventure et al, 2001). The phenotype observed in dwarfism suggests that the dysregulation of FGFR3 could impair cell growth and differentiation (Su et al, 1997;LegeaiMallet et al, 1998;Sahni et al, 1999), knockout mouse studies confirming an inhibitory role for FGFR3 in bone growth (Colvin et al, 1996;Deng et al, 1996). However, FGFR3 may regulate differentiation (Kobrin et al, 1993;Kanai et al, 1997) or apoptosis (Plowright et al, 2000) dependent on the tissue type, consistent with a multifunctional role of FGFR3.…”