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

• Published in: Human molecular genetics 2006-06, Vol.15 (11), p.1783-1792
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Aggrecans; Animals; Arthritis - genetics; Arthritis - pathology; Biological and medical sciences; Cartilage - metabolism; Cartilage Diseases - metabolism; Cartilage, Articular - metabolism; Cell receptors; Cell structures and functions; Chondrocytes - metabolism; Chondroitin Sulfate Proteoglycans - metabolism; Collagen Type II - metabolism; Collagen Type X - metabolism; Collagenases - biosynthesis; Crosses, Genetic; Diseases of the osteoarticular system; Epitopes - chemistry; Extracellular Matrix Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Lectins, C-Type - metabolism; Matrix Metalloproteinase 13; Medical sciences; Mice; Mice, Transgenic; Miscellaneous; Miscellaneous. Osteoarticular involvement in other diseases; Molecular and cellular biology; Osteoblasts - metabolism; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Signal Transduction
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddl100

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.