Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis.
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 (DeltaDS-DDR-2) or the protein tyrosine kinase (PTK) core (DeltaPTK-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 alpha2beta1 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 alpha2beta1 integrin and the interleukin-1-induced signaling pathways in chondrocytes.


CONCLUSIONS
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.
Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
Lin
L
Xu
Haibing
H
Peng
Sonya
S
Glasson
Peter L
PL
Lee
Kenpan
K
Hu
Kosei
K
Ijiri
Bjorn R
BR
Olsen
Mary B
MB
Goldring
Yefu
Y
Li
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D024043:Collagen Type II / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005270:Femur Head / Q000473:pathology; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D013264:Stifle / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D024043:Collagen Type II; D004791:Enzyme Inhibitors; D038982:Integrin alpha2beta1; D007375:Interleukin-1; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D053509:Matrix Metalloproteinase 13