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PMID:15781473

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Citation

Davidson, D, Blanc, A, Filion, D, Wang, H, Plut, P, Pfeffer, G, Buschmann, MD and Henderson, JE (2005) Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J. Biol. Chem. 280:20509-15

Abstract

Signaling by fibroblast growth factor (FGF) 18 and FGF receptor 3 (FGFR3) have been shown to regulate proliferation, differentiation, and matrix production of articular and growth plate chondrocytes in vivo and in vitro. Notably, the congenital absence of either FGF18 or FGFR3 resulted in similar expansion of the growth plates of fetal mice and the addition of FGF18 to human articular chondrocytes in culture enhanced proliferation and matrix production. Based on these and other experiments it has been proposed that FGF18 signals through FGFR3 to promote cartilage production by chondrocytes. Its role in chondrogenesis remains to be defined. In the current work we used the limb buds of FGFR3(+/+) and FGFR3(-/-) embryonic mice as a source of mesenchymal cells to determine how FGF18 signaling affects chondrogenesis. Confocal laser-scanning microscopy demonstrated impaired cartilage nodule formation in the FGFR3(-/-) cultures. Potential contributing factors to the phenotype were identified as impaired mitogenic response to FGF18, decreased production of type II collagen and proteoglycan in response to FGF18 stimulation, impaired interactions with the extracellular matrix resulting from altered integrin receptor expression, and altered expression of FGFR1 and FGFR2. The data identified FGF18 as a selective ligand for FGFR3 in limb bud mesenchymal cells, which suppressed proliferation and promoted their differentiation and production of cartilage matrix. This work, thus, identifies FGF18 and FGFR3 as potential molecular targets for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage.

Links

PubMed Online version:10.1074/jbc.M410148200

Keywords

Animals; Cartilage/cytology; Cartilage/embryology; Cell Differentiation/drug effects; Cell Division/drug effects; Cells, Cultured; Chondrocytes/cytology; Chondrogenesis/physiology; Collagen Type II/analysis; Collagen Type X/genetics; Extremities/embryology; Female; Fibroblast Growth Factors/pharmacology; Fibroblast Growth Factors/physiology; Fluorescent Antibody Technique; Gene Expression/drug effects; Ligands; Male; Mesenchymal Stem Cells/cytology; Mice; Mice, Knockout; Microscopy, Confocal; Protein-Tyrosine Kinases/deficiency; Protein-Tyrosine Kinases/genetics; Protein-Tyrosine Kinases/physiology; RNA, Messenger/analysis; Receptor, Fibroblast Growth Factor, Type 3; Receptors, Fibroblast Growth Factor/deficiency; Receptors, Fibroblast Growth Factor/genetics; Receptors, Fibroblast Growth Factor/physiology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FGF18

acts_upstream_of_or_within

GO:0032332: positive regulation of chondrocyte differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95524

P

  • occurs_in:(EMAPA:17244)
  • regulates_o_results_in_acquisition_of_features_of:(CL:0000138)

Seeded From UniProt

complete

MOUSE:FGF18

acts_upstream_of_or_within

GO:0008543: fibroblast growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95524

P

  • occurs_in:(CL:0000134)
  • occurs_in:(EMAPA:17244)

Seeded From UniProt

complete

MOUSE:FGF2

acts_upstream_of_or_within

GO:0045597: positive regulation of cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:17244)
  • regulates_o_results_in_acquisition_of_features_of:(CL:0000134)

Seeded From UniProt

complete

MOUSE:FGFR3

acts_upstream_of_or_within

GO:0008543: fibroblast growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1277980

P

  • occurs_in:(CL:0000134)
  • occurs_in:(EMAPA:17244)

Seeded From UniProt

complete

MOUSE:FGFR3

acts_upstream_of_or_within

GO:0051216: cartilage development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931521

P

Seeded From UniProt

complete


See also

References

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