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Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells: Regulation by tumor necrosis factor-α and doxycycline

Author: Hanemaaijer, R. · Sorsa, T. · Konttinen, Y.T. · Ding, Y. · Sutinen, M. · Visser, H. · Hinsbergh, V.W.M. van · Helaakoski, T. · Kainulainen, T. · Rönkä, H. · Tschesche, H. · Salo, T.
Type:article
Date:1997
Institution: Gaubius Instituut TNO
Source:Journal of Biological Chemistry, 50, 272, 31504-31509
Identifier: 234274
doi: doi:10.1074/jbc.272.50.31504
Keywords: Arthritis, Rheumatoid · Catalysis · Cells, Cultured · Collagenases · Doxycycline · Endothelium · Endothelium, Vascular · Enzyme Inhibitors · Fibroblasts · Glycosylation · Humans · Matrix Metalloproteinase 8 · RNA, Messenger · Synovial Membrane · Tetradecanoylphorbol Acetate · Tumor Necrosis Factor-alpha · Up-Regulation

Abstract

Neutrophil collagenase (matrix metalloproteinase-8 or MMP-8) is regarded as being synthesized exclusively by polymorphonuclear neutrophils (PMN). However, in vivo MMP-8 expression was observed in mononuclear fibroblast- like cells in the rheumatoid synovial membrane. In addition, we detected MMP- 8 mRNA expression in cultured rheumatoid synovial fibroblasts and human endothelial cells. Up-regulation of MMP-8 was observed after treatment of the cells with either tumor necrosis factor-α (10 ng/ml) or phorbol 12-myristate 13-acetate (10 nM). Western analysis showed a similar regulation at the protein level. The size of secreted MMP-8 was 50 kDa, which is about 30 kDa smaller than MMP-8 from PMN. Conditioned media from rheumatoid synovial fibroblasts contained both type I and II collagen degrading activity. However, degradation of type II collagen, but not that of type I collagen, was completely inhibited by 50 μM doxycycline, suggesting specific MMP-8 activity. In addition, doxycycline down-regulated MMP-8 induction, at both the mRNA and protein levels. Thus MMP-8 exerts markedly wider expression in human cells than had been thought previously, implying that PMN are not the only source of cartilage degrading activity at arthritic sites. The inhibition of both MMP-8 activity and synthesis by doxycycline provides an incentive for further studies on the clinical effects of doxycycline in the treatment of rheumatoid arthritis.