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Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice

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Author: Valverde-Franco, G. · Binette, J.S. · Li, W. · Wang, H. · Chai, S. · Laflamme, F. · Tran-Khanh, N. · Quenneville, E. · Meijers, T. · Poole, A.R. · Mort, J.S. · Buschmann, M.D. · Henderson, J.E.
Institution: TNO Kwaliteit van Leven
Source:Human Molecular Genetics, 11, 15, 1783-1792
Identifier: 239296
doi: doi:10.1093/hmg/ddl100
Keywords: Collagenase 3 · Core protein · Epitope · Fibroblast growth factor receptor 3 · Proteoglycan · Animal cell · Animal experiment · Animal model · Animal tissue · Cartilage degeneration · Cartilage matrix · Cell structure · Compression · Controlled study · Genetic procedures · Humerus head · Hypertrophy · Immunoreactivity · Mouse · Nonhuman · Physical resistance · Protein deficiency · Protein degradation · Protein expression · Protein targeting · Rigidity · Signal transduction · Synovium · Tissue metabolism · Aggrecans · Animals · Arthritis · Cartilage · Cartilage Diseases · Cartilage, Articular · Chondrocytes · Collagen Type II · Collagen Type X · Collagenases · Crosses, Genetic · Epitopes · Extracellular Matrix Proteins · Lectins, C-Type · Matrix Metalloproteinase 13 · Mice · Mice, Transgenic · Osteoblasts · Proteochondroitin Sulfates · Receptor, Fibroblast Growth Factor, Type 3 · Signal Transduction


Fibroblast growth factor (FGF) receptor 3 has been identified as a key regulator of endochondral bone development and of post-natal bone metabolism through its action on growth plate chondrocytes and osteoblasts, respectively. It has also been shown to promote chondrogenesis and cartilage production by cultured pre-chondrogenic cells in response to FGF18. In the current studies, we show that the absence of signaling through Fgfr3 in the joints of Fgfr3-/- mice leads to premature cartilage degeneration and early arthritis. Degenerative changes in cartilage matrix included excessive proteolysis of aggrecan core protein and type II collagen, as measured by neo-epitope immunoreactivity. These changes were accompanied by increased expression of metalloproteinase MMP13, type X collagen, cellular hypertrophy and loss of proteoglycan at the articular surface. Using a novel micro-mechanical indentation protocol, it was shown that articular cartilage in the humeral head of 4-month-old Ffr3-/- mice was less resistant to compressive force and less stiff than that of littermate controls. These results identify Fgfr3 signaling as a potential target for intervention in degenerative disorders of cartilage metabolism. © 2006 Oxford University Press. Chemicals / CAS: collagenase 3, 175449-82-8; fibroblast growth factor receptor 3, 306781-00-0; Agc1 protein, mouse; Aggrecans; Collagen Type II; Collagen Type X; Collagenases, EC 3.4.24.-; Epitopes; Extracellular Matrix Proteins; Lectins, C-Type; Matrix Metalloproteinase 13, EC 3.4.24.-; Mmp13 protein, mouse, EC 3.4.24.-; Proteochondroitin Sulfates; Receptor, Fibroblast Growth Factor, Type 3, EC