Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice.
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.
Valverde-Franco
G
G
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.
Binette
J S
JS
Li
W
W
Wang
H
H
Chai
S
S
Laflamme
F
F
Tran-Khanh
N
N
Quenneville
E
E
Meijers
T
T
Poole
A R
AR
Mort
J S
JS
Buschmann
M D
MD
Henderson
J E
JE
D053674:Aggrecans; D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000473:pathology*; D002356:Cartilage / Q000378:metabolism; D002357:Cartilage Diseases / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D024121:Collagen Type X / Q000378:metabolism; D017364:Collagenases / Q000096:biosynthesis; D003433:Crosses, Genetic; D000939:Epitopes / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D015398:Signal Transduction
C508320:Acan protein, mouse; D053674:Aggrecans; D011508:Chondroitin Sulfate Proteoglycans; D024043:Collagen Type II; D024121:Collagen Type X; D000939:Epitopes; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse