Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis.

Abstract

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.

• Authors: Jin Su, Jiangtian Yu, Tingting Ren, Wei Zhang, Yuanqiang Zhang, Xinping Liu, Tiezheng Sun, Houshan Lu, Keiji Miyazawa, Libo Yao
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 330 Issue 1-2 Pg. 141-52 (Oct 2009) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 19415460 (Publication Type: Journal Article)

Chemical References

• Collagen Type II
• Receptors, Mitogen
• Discoidin Domain Receptors
• Receptor Protein-Tyrosine Kinases
• Matrix Metalloproteinase 13

Topics

• Animals
• Arthritis, Rheumatoid (pathology)
• Binding Sites
• Collagen Type II (pharmacology)
• Discoidin Domain Receptors
• Extracellular Matrix
• Fibroblasts (pathology)
• Humans
• Matrix Metalloproteinase 13 (genetics)
• Mice
• Receptor Protein-Tyrosine Kinases (genetics, physiology)
• Receptors, Mitogen (genetics, physiology)
• Synovial Membrane (pathology)
• Up-Regulation