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
J.T.N. Wong Laboratories for Mineralized Tissue Research, and Centre for Bone and Periodontal Research, McGill University, 740 Avenue Dr Penfield, Montreal H3A 1A4, Quebec, Canada.
Hum Mol Genet. 2006 Jun 1;15(11):1783-92. doi: 10.1093/hmg/ddl100. Epub 2006 Apr 19.
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.
成纤维细胞生长因子（FGF）受体3已被确定为软骨内骨发育以及出生后骨代谢的关键调节因子，它分别通过作用于生长板软骨细胞和成骨细胞来发挥作用。研究还表明，在FGF18的作用下，培养的软骨前体细胞通过Fgfr3发出的信号可促进软骨形成和软骨生成。在当前的研究中，我们发现Fgfr3基因敲除（Fgfr3(-/-)）小鼠关节中缺乏通过Fgfr3发出的信号会导致软骨过早退化和早期关节炎。通过新表位免疫反应性检测发现，软骨基质的退行性变化包括聚集蛋白聚糖核心蛋白和II型胶原的过度蛋白水解。这些变化伴随着金属蛋白酶MMP13、X型胶原表达增加，细胞肥大以及关节表面蛋白聚糖丢失。使用一种新型的微机械压痕实验方法，结果显示4月龄Fgfr3(-/-)小鼠肱骨头的关节软骨比同窝对照小鼠的软骨对压缩力的抵抗力更弱且硬度更低。这些结果表明，Fgfr3信号传导是干预软骨代谢退行性疾病的一个潜在靶点。
