Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis

• Published in: Arthritis and rheumatism Vol. 56; no. 8; pp. 2663 - 2673
• Main Authors: Xu, Lin, Peng, Haibing, Glasson, Sonya, Lee, Peter L., Hu, Kenpan, Ijiri, Kosei, Olsen, Bjorn R., Goldring, Mary B., Li, Yefu
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2007; Wiley
• Subjects: Animals; Biological and medical sciences; Biomarkers - metabolism; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Cells, Cultured; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - pathology; Collagen Type II - metabolism; Discoidin Domain Receptors; Disease Models, Animal; Disease Progression; Diseases of the osteoarticular system; Enzyme Inhibitors - pharmacology; Femur Head - pathology; Humans; Injuries of the limb. Injuries of the spine; Integrin alpha2beta1 - metabolism; Interleukin-1 - metabolism; Male; Matrix Metalloproteinase 13 - metabolism; Medical sciences; Mice; Mice, Inbred Strains; Miscellaneous. Osteoarticular involvement in other diseases; Osteoarthritis; Osteoarthritis - genetics; Osteoarthritis - metabolism; Osteoarthritis - pathology; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Mitogen - genetics; Receptors, Mitogen - metabolism; Stifle - metabolism; Stifle - pathology; Traumas. Diseases due to physical agents; Knee; Human; Immunohistochemistry; Tyrosine; Alanine; Chondrocyte; Femoral head; Pathogenesis; Diseases of the osteoarticular system; Fracture; Joint; Trauma; Polymerase chain reaction; Anatomic pathology; Articular cartilage; Aminoacid; Animal; Collagen; Arthropathy; Degenerative disease; Molecular biology; Osteoarthritis
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.22761

Objective To investigate the role of the collagen receptor discoidin domain receptor 2 (DDR‐2) in the pathogenesis of osteoarthritis (OA). Methods Histologic and immunohistochemical analyses were performed to characterize femoral head cartilage from 7 patients with OA and 4 patients with fracture, as well as articular cartilage from the knee joints of mice with surgically induced OA. Gene constructs encoding human Raf kinase inhibitor protein (RKIP), DDR‐2 lacking the discoidin (DS) domain (ΔDS‐DDR‐2) or the protein tyrosine kinase (PTK) core (ΔPTK‐DDR‐2), DDR‐2 containing a substitution of tyrosine for alanine at position 740 (Y740A), and luciferase driven by the matrix metalloproteinase 13 (MMP‐13) promoter were transfected into human chondrocyte cell lines. Activated and neutralized α2β1 integrin polyclonal antibodies, interleukin‐1 receptor antagonist, and the chemical inhibitors SB203580, for p38, and SP600125, for JNKs, were used in cell cultures. Real‐time polymerase chain reaction was performed to examine MMP‐13 and DDR‐2 messenger RNA (mRNA). Results Increased immunostaining for DDR‐2, MMP‐13, and MMP‐derived type II collagen fragments was detected in cartilage from patients with OA and from mice with surgically induced OA. The discoidin domain and PTK core of DDR‐2 were essential for signal transmission and the resulting increased expression of MMP‐13 in chondrocytes. Y740A mutation of DDR‐2 reduced levels of mRNA for MMP‐13 and endogenous DDR‐2. The overexpression of RKIP or preincubation with the p38 inhibitor reduced MMP‐13 mRNA levels. DDR‐2 signaling was independent of the α2β1 integrin and the interleukin‐1–induced signaling pathways in chondrocytes. Conclusion These findings suggest that increased expression of DDR‐2, resulting in the elevated expression of MMP‐13, may be one of the common events in OA progression.