Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis.
Regulation of matrix metalloproteinase-13 (MMP-13) by collagen matrix in the synovial fibroblasts of rheumatoid arthritis (RA) is critical event in the progressive joint destruction. Our previous study indicated that a collagen receptor, discoidin receptor 2 (DDR2), was highly expressed in the synovial fibroblasts of RA. However, the functional role of DDR2 in the regulation of MMP-13 production in synovial fibroblasts has not been elucidated. In this study, we initially demonstrated that the DDR2 and MMP-13 proteins are both highly expressed in the synovial lining layer of RA. MMP-13 mRNA and protein in synovial fibroblasts of RA were preferentially induced by collagen type II compared with MMP-1. Furthermore, stable overexpression of wild type DDR2 in murine synoviocytes dramatically augments the production of MMP-13. The activation of DDR2 also mediates the up-regulation of MMP-13 promoter activity in 293T cells. Inhibitor specific for extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) cascade was shown to decrease MMP-13 level induced by collagen II in RA synovial fibroblasts and DDR2-induced MMP-13 promoter activity. Runx2 and activator protein-1 (AP-1) binding sites in MMP-13 promoter region are required for DDR2-induced transcription. The data in this study suggest that DDR2-mediated MMP-13 induction by collagen matrix in synovial fibroblasts of RA contributed to articular cartilage destruction.
Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi, 710032, People's Republic of China.
Jin
J
Su
Jiangtian
J
Yu
Tingting
T
Ren
Wei
W
Zhang
Yuanqiang
Y
Zhang
Xinping
X
Liu
Tiezheng
T
Sun
Houshan
H
Lu
Keiji
K
Miyazawa
Libo
L
Yao
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D001665:Binding Sites; D024043:Collagen Type II / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D005109:Extracellular Matrix; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000235:genetics*; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D011975:Receptors, Mitogen / Q000235:genetics* / Q000502:physiology*; D013583:Synovial Membrane / Q000473:pathology*; D015854:Up-Regulation
D024043:Collagen Type II; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D053509:Matrix Metalloproteinase 13