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.
Su
Jin
J
Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi, 710032, People's Republic of China.
Yu
Jiangtian
J
Ren
Tingting
T
Zhang
Wei
W
Zhang
Yuanqiang
Y
Liu
Xinping
X
Sun
Tiezheng
T
Lu
Houshan
H
Miyazawa
Keiji
K
Yao
Libo
L
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