Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells - Regulation by tumor necrosis factor-alpha and doxycycline
Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells - Regulation by tumor necrosis factor-alpha and doxycycline
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DOI：
10.1074/jbc.272.50.31504
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发表时间：
1997-12-12
影响因子：
4.8
通讯作者：
Salo, T
中科院分区：
文献类型：
--
作者：
Hanemaaijer, R;Sorsa, T;Salo, T
中性粒细胞胶原酶（基质金属蛋白酶-8或MMP-8）被认为是由多形核中性粒细胞（PMN）专门合成的。然而，在体内MMP-8的表达中观察到单核成纤维细胞样细胞在类风湿性滑膜。此外，我们还检测了MMP-8 mRNA在培养的类风湿滑膜成纤维细胞和人内皮细胞中的表达。在用肿瘤坏死因子-α（10 ng/ml）或佛波醇12-肉豆蔻酸酯13-乙酸酯（10 nM）处理细胞后观察到MMP-8的上调。Western分析表明，在蛋白质水平上也有类似的调节作用。分泌的MMP-8的大小为50 kDa，这比来自PMN的MMP-8小约30 kDa。来自类风湿性滑液成纤维细胞的条件培养基含有I型和II型胶原降解活性。然而，II型胶原蛋白的降解，但不是I型胶原蛋白的降解，被50 μ M强力霉素完全抑制，这表明特定的MMP-8活性。此外，强力霉素下调MMP-8的诱导，在mRNA和蛋白质水平。因此，MMP-8在人类细胞中的表达明显比以前认为的更广泛，这意味着PMN不是关节炎部位软骨降解活性的唯一来源。多西环素对MMP-8活性和合成的抑制为进一步研究多西环素治疗类风湿关节炎的临床效果提供了动力。
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-alpha (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 mu M 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.