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Human Molecular Genetics Advance Access published online on April 19, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl100
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received February 14, 2006
Revised April 5, 2006
Accepted April 5, 2006

Article

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

G. Valverde-Franco 1, J. S. Binette 2, W. Li 1, H. Wang 1, S. Chai 1, F. Laflamme 3, N. Tran-Khanh 4, E. Quenneville 4, T. Meijers 5, A. R. Poole 6, J. S. Mort 6, M. D. Buschmann 4, and J. E. Henderson 7 *

1 J.T.N. Wong Laboratories for Mineralized Tissue Research; Centre for Bone and Periodontal Research, McGill University, Montréal, Québec, Canada
2 Centre for Bone and Periodontal Research, McGill University, Montréal, Québec, Canada
3 Departments of Engineering Physics
4 Departments of Chemical Engineering, école Polytechnique, Montréal, Québec, Canada
5 TNO Pharma, Utrechtseweg 48, The Netherlands
6 Joint Diseases Laboratory, Shriner's Hospital for Children
7 Faculty of Medicine, McGill University, J.T.N. Wong Laboratories for Mineralized Tissue Research, Centre for Bone and Periodontal Research, 740 Ave Dr Penfield, Room 2200, Montreal H3A 1A4

* To whom correspondence should be addressed.
J. E. Henderson, E-mail: janet.henderson{at}mcgill.ca


  Abstract

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 signalling 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 neoepitope immunoreactivity. These changes were accompanied by increased expression of 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 four 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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