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Human Molecular Genetics Advance Access originally published online on April 19, 2006
Human Molecular Genetics 2006 15(11):1783-1792; doi:10.1093/hmg/ddl100
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

G. Valverde-Franco1,3, J.S. Binette3, W. Li1,3, H. Wang1,3, S. Chai1,3, F. Laflamme4, N. Tran-Khanh5, E. Quenneville5, T. Meijers6, A.R. Poole2, J.S. Mort2, M.D. Buschmann5 and J.E. Henderson1,3,*

1J.T.N. Wong Laboratories for Mineralized Tissue Research, 2Joint Diseases Laboratory, Shriner’s Hospital for Children and 3Centre for Bone and Periodontal Research, McGill University, Montréal, Québec, Canada, 4Department of Engineering Physics and 5Department of Chemical Engineering, École Polytechnique, Montréal, Québec, Canada and 6TNO Pharma, Utrechtseweg 48, The Netherlands

* To whom correspondence should be addressed at: J.T.N. Wong Laboratories for Mineralized Tissue Research and Centre for Bone and Periodontal Research, McGill University, 740 Ave Dr Penfield, Room 2200, Montreal H3A 1A4, Québec, Canada. Tel: +1 5143983523; Email: janet.henderson{at}mcgill.ca

Received February 14, 2006; Accepted April 5, 2006

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 Fgfr3–/– 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.


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