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© The Rockefeller University Press, 0021-9525/2003/6/1053 $5.00
The Journal of Cell Biology, Volume 161, Number 6, 1053-1066

A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation

Department of Microbiology, New York University School of Medicine, New York, NY 10016

Address correspondence to C. Basilico, Dept. of Microbiology, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Tel.: (212) 263-5341. Fax: (212) 263-8714. E-mail: basilc01{at}med.nyu.edu; or L. Dailey, Dept. of Microbiology, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Tel.: (212) 263-5341. Fax: (212) 263-8714. E-mail: dailel01{at}med.nyu.edu

Activating mutations in FGF receptor 3 (FGFR3) cause several human dwarfism syndromes by affecting both chondrocyte proliferation and differentiation. Using microarray and biochemical analyses of FGF-treated rat chondrosarcoma chondrocytes, we show that FGF inhibits chondrocyte proliferation by initiating multiple pathways that result in the induction of antiproliferative functions and the down-regulation of growth-promoting molecules. The initiation of growth arrest is characterized by the rapid dephosphorylation of the retinoblastoma protein (pRb) p107 and repression of a subset of E2F target genes by a mechanism that is independent of cyclin E–Cdk inhibition. In contrast, hypophosphorylation of pRb and p130 occur after growth arrest is first detected, and may contribute to its maintenance. Importantly, we also find a number of gene expression changes indicating that FGF promotes many aspects of hypertrophic differentiation, a notion supported by in situ analysis of developing growth plates from mice expressing an activated form of FGFR3. Thus, FGF may coordinate the onset of differentiation with chondrocyte growth arrest in the developing growth plate.

Key Words: DNA; microarrays; E2F; retinoblastoma proteins; Cdk

^* Abbreviations used in this paper: CDKI, Cdk inhibitor; FGFR3, FGF receptor 3; Ihh, Indian hedgehog; MMP13, matrix metalloproteinase 13; OPG, osteoprotegerin; OPN, osteopontin; pRb, retinoblastoma protein; RCS, rat chondrosarcoma.

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