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Research Article |
1 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot
76100, Israel
2 ProChon Biotech Ltd, Kiryat Weizmann, Rehovot 76114, Israel
Author for correspondence (e-mail: yayon{at}prochon.co.il)
Accepted 10 October 2001
The effect of fibroblast growth factor (FGF) on mature chondrocytes, the
cells responsible for axial skeletal development, is growth attenuation rather
than stimulation. This singular response has been linked to signaling via FGF
receptor 3 (FGFR3), partly because mutations causing chronic FGFR3 activation
lead to various human disorders of bone growth. In order to study how FGF
inhibits growth, we analyzed its effect on a rat chondrocyte-derived cell
line. We show that the FGF-induced growth arrest occurs at the G1 phase,
accompanied by profound changes in gene expression and cytoskeletal
organization. Within minutes of binding, FGF induces tyrosine kinase activity
in the focal substrate adhesions where it colocalizes with vinculin. Upon FGF
stimulation, FGFR3 is selectively removed from the focal adhesions, which is
followed by their disassembly and disruption of the organized cytoskeleton.
Multiple genes are induced following FGF stimulation in chondrocytes, which
has been shown by DNA array screening and confirmed for some by
immunoblotting. These genes include regulators of cell differentiation and
proliferation such as c-jun, JunD, cyclin-D1, NF
B1 and of
plasma-membrane microdomain morphology, such as ezrin. The transcription
factor Id1 is downregulated, consistent with the cells' exit from the mitotic
cycle. Moreover, following FGF stimulation, levels of FGFR3 mRNA and protein
decline, as does downstream signaling through the MAPK pathway. The importance
of this FGFR3-mediated on-off control is illustrated in transgenic mice
expressing mutant, hyperactive FGFR3, where abnormally high levels of
NFB are expressed throughout their bone growth-plates. A working model
is presented of the signaling network involved in regulating FGF-induced
chondrocyte differentiation and receptor downregulation.
Key words: Chondrocytes, FGF signaling, FGF receptor 3, Focal adhesions, G1 arrest
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