ARTHRITIS & RHEUMATISM Vol. 56, No. 8, August 2007, pp 2663–2673 DOI 10.1002/art.22761 © 2007, American College of Rheumatology Increased Expression of the Collagen Receptor Discoidin Domain Receptor 2 in Articular Cartilage as a Key Event in the Pathogenesis of Osteoarthritis Lin Xu, 1 Haibing Peng, 2 Sonya Glasson, 3 Peter L. Lee, 1 Kenpan Hu, 1 Kosei Ijiri, 2 Bjorn R. Olsen, 4 Mary B. Goldring, 2 and Yefu Li 1 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 con- structs encoding human Raf kinase inhibitor protein (RKIP), DDR-2 lacking the discoidin (DS) domain (DS-DDR-2) or the protein tyrosine kinase (PTK) core (PTK-DDR-2), DDR-2 containing a substitu- tion 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 21 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 expres- sion of MMP-13 in chondrocytes. Y740A mutation of DDR-2 reduced levels of mRNA for MMP-13 and en- dogenous DDR-2. The overexpression of RKIP or pre- incubation with the p38 inhibitor reduced MMP-13 mRNA levels. DDR-2 signaling was independent of the 21 integrin and the interleukin-1–induced signaling pathways in chondrocytes. Conclusion. These findings suggest that increased expression of DDR-2, resulting in the elevated expres- sion of MMP-13, may be one of the common events in OA progression. Osteoarthritis (OA), the most common form of arthritis (1,2), is considered to be a group of overlap- ping, distinct diseases associated with different risk factors but with a similar clinical outcome. The patho- logic changes during the development of OA are re- markably similar and include proteoglycan degradation at the early stage, followed by type II collagen degrada- tion, leading eventually to localized or complete loss of cartilage matrix (3). The similar pathologic changes suggest that a common molecular chain of events may be responsible for the disease progression. An understand- ing of these molecular events will not only elucidate Dr. Xu’s work was supported by NIH grant R01-AR-051989. Dr. Olsen’s work was supported by NIH grant R01-AR-36819. Dr. Goldring’s work was supported by NIH grant R01-AG-22021. Dr. Li’s work was supported by NIH grants R01-AR-051989 and P01-AR- 050245. 1 Lin Xu, MD, PhD, Peter L. Lee, Kenpan Hu, DDS, Yefu Li, MD, PhD: Harvard School of Dental Medicine, Boston, Massachu- setts; 2 Haibing Peng, MD, Kosei Ijiri, MD, PhD, Mary B. Goldring, PhD: Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, and Harvard Medical School, Boston, Massachusetts; 3 Sonya Glasson, DVM: Wyeth Research, Cambridge, Massachusetts; 4 Bjorn R. Olsen, MD, PhD: Harvard School of Dental Medicine, and Harvard Medical School, Boston, Massachusetts. Dr. Glasson owns stock or stock options in Wyeth and is inventor with Wyeth on a patent for ADAMTS small-molecule inhib- itors. Address correspondence and reprint requests to Yefu Li, MD, PhD, or Lin Xu, MD, PhD, Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115. E-mail: yefu_li@hms.harvard.edu, or lin_xu@ hms.harvard.edu. Submitted for publication August 20, 2006; accepted in revised form April 20, 2007. 2663