Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone and Bones / cytology
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Bone and Bones / embryology*
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Bone and Bones / metabolism
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Cartilage / embryology*
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Cartilage / growth & development
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Cartilage / metabolism
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Cell Cycle Proteins*
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Cell Differentiation / genetics
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Cell Division / genetics
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Chondrocytes / cytology
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Chondrocytes / metabolism*
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Cyclin E / genetics
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Cyclin E / metabolism
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DNA-Binding Proteins*
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Down-Regulation / genetics
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E2F Transcription Factors
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Fibroblast Growth Factors / metabolism*
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Fibroblast Growth Factors / pharmacology
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Gene Expression Regulation, Developmental / genetics
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Genes, Regulator / genetics
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Mice
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Mice, Transgenic
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Osteogenesis / genetics*
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Protein-Tyrosine Kinases*
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Rats
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Receptor, Fibroblast Growth Factor, Type 3
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Receptors, Fibroblast Growth Factor / genetics
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Receptors, Fibroblast Growth Factor / metabolism
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Retinoblastoma-Like Protein p107
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Signal Transduction / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
Substances
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Cell Cycle Proteins
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Cyclin E
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DNA-Binding Proteins
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E2F Transcription Factors
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Nuclear Proteins
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Rbl1 protein, mouse
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Receptors, Fibroblast Growth Factor
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Retinoblastoma-Like Protein p107
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Transcription Factors
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Fibroblast Growth Factors
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Fgfr3 protein, mouse
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Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 3