ab21504

Influence of hypoxia on the expression of matrix metalloproteinase-1, -3 and tissue inhibitor of metalloproteinase-1 in rheumatoid synovial fibroblasts

H.-S. Cha, K.-S. Ahn¹, C. H. Jeon, J. Kim¹, Y. W. Song², E.-M. Koh

Department of Medicine, Samsung Medical Center and ¹Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine; ²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
Objective
The rheumatoid synovium is a hypoxic environment, and hypoxia has been implicated as a factor in the pathogenesis of rheumatoid arthritis (RA). The purpose of this study was to investigate the effect of hypoxia on the expression of matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of metalloproteinase (TIMP)-1 in rheumatoid synovial fibroblasts.

Methods
Synovial fibroblasts obtained from RA patients were cultured for 48 h under normoxic or hypoxic conditions. Assays included western blot analysis and enzyme-linked immunosorbent assay (ELISA) for MMP-1, -3 and TIMP-1, and northern blot analysis to measure TIMP-1 mRNA levels.

Results
Compared with normoxic culture, hypoxia increased MMP-1 and MMP-3 expression in rheumatoid synovial fibroblasts. Hypoxia decreased TIMP-1 expression in rheumatoid synovial fibroblasts, as measured by both protein and mRNA levels.

Conclusion
These results suggest that microenvironmental conditions, such as hypoxia, may directly contribute to joint destruction in RA by increasing the ratio of MMP-1, -3 to TIMP-1 production in synovial fibroblasts.

Key words
Hypoxia, rheumatoid arthritis, matrix metalloproteinase, tissue inhibitor of metalloproteinase.

Please address reprint requests and correspondence to: Eun-Mi Koh, MD, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea.
E-mail: chahs@samsung.co.kr