Induction of multiple matrix metalloproteinases in human dermal and synovial fibroblasts by Staphylococcus aureus:: implications in the pathogenesis of septic arthritis and other soft tissue infections
Induction of multiple matrix metalloproteinases in human dermal and synovial fibroblasts by Staphylococcus aureus:: implications in the pathogenesis of septic arthritis and other soft tissue infections
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DOI：
10.1186/ar2086
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发表时间：
2006-01-01
影响因子：
4.9
通讯作者：
Schaberg, Dennis
中科院分区：
文献类型：
--
作者：
Kanangat, Siva;Postlethwaite, Arnold;Schaberg, Dennis
金黄色葡萄球菌感染身体组织后，结缔组织迅速降解。类风湿性关节炎患者更容易患S。金黄色葡萄球菌介导的脓毒性关节炎。各种类型的胶原蛋白形成身体不同结缔组织的主要结构基质。这些不同的胶原蛋白被特定的基质金属蛋白酶（MMP）降解，所述基质金属蛋白酶由成纤维细胞、其他结缔组织细胞和由白细胞介素-1（IL-1）和肿瘤坏死因子（TNF）诱导的炎性细胞产生。为了确定宿主在共同破坏S.金黄色葡萄球菌介导的化脓性关节炎，我们分析了MMP表达的人皮肤和滑膜成纤维细胞暴露于培养上清液和全细胞裂解物的S。金黄色。与未处理的对照相比，用细胞裂解物和过滤的培养上清液处理的人皮肤和滑膜成纤维细胞具有显著增强的MMP-1、MMP-2、MMP-3、MMP-7、MMP-10和MMP-11的表达（p < 0.05）。在S.在金黄色葡萄球菌培养物上清液中，MMP诱导活性被鉴定为在30至>50 kDa的分子量范围内。MMP表达谱在暴露于IL-1/TNF组合的成纤维细胞中相似。在S处理的成纤维细胞中，有丝分裂原活化蛋白激酶（MAPK）信号转导途径的几个基因的mRNA水平显着升高。金黄色葡萄球菌细胞裂解物和培养物上清液。此外，酪氨酸磷酸化显着较高的成纤维细胞处理S。金黄色组分。酪氨酸磷酸化和MAPK基因表达模式在IL-1/TNF和S.金黄色。缺乏葡萄球菌辅助调节因子（Sar）和辅助基因调节因子（Agr）的突变体在小鼠模型中引起严重程度明显降低的脓毒性关节炎，能够诱导与其同基因亲本菌株相当的几种MMP mRNA的表达，但诱导明显更高水平的金属蛋白酶组织抑制剂（TIMP）。据我们所知，这是第一个报告，诱导多个MMP/TIMP表达从人皮肤和滑膜成纤维细胞在S。金黄色葡萄球菌处理。我们认为宿主来源的MMPs促进了在S.金黄色葡萄球菌介导的脓毒性关节炎。
Infections of body tissue by Staphylococcus aureus are quickly followed by degradation of connective tissue. Patients with rheumatoid arthritis are more prone to S. aureus-mediated septic arthritis. Various types of collagen form the major structural matrix of different connective tissues of the body. These different collagens are degraded by specific matrix metalloproteinases (MMPs) produced by fibroblasts, other connective tissue cells, and inflammatory cells that are induced by interleukin-1 (IL-1) and tumor necrosis factor (TNF). To determine the host's contribution in the joint destruction of S. aureus-mediated septic arthritis, we analyzed the MMP expression profile in human dermal and synovial fibroblasts upon exposure to culture supernatant and whole cell lysates of S. aureus. Human dermal and synovial fibroblasts treated with cell lysate and filtered culture supernatants had significantly enhanced expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-10, and MMP-11 compared with the untreated controls (p < 0.05). In the S. aureus culture supernatant, the MMP induction activity was identified to be within the molecular-weight range of 30 to >50 kDa. The MMP expression profile was similar in fibroblasts exposed to a combination of IL-1/TNF. mRNA levels of several genes of the mitogen-activated protein kinase (MAPK) signal transduction pathway were significantly elevated in fibroblasts treated with S. aureus cell lysate and culture supernatant. Also, tyrosine phosphorylation was significantly higher in fibroblasts treated with S. aureus components. Tyrosine phosphorylation and MAPK gene expression patterns were similar in fibroblasts treated with a combination of IL-1/TNF and S. aureus. Mutants lacking staphylococcal accessory regulator (Sar) and accessory gene regulator (Agr), which cause significantly less severe septic arthritis in murine models, were able to induce expression of several MMP mRNA comparable with that of their isogenic parent strain but induced notably higher levels of tissue inhibitors of metalloproteinases (TIMPs). To our knowledge, this is the first report of induction of multiple MMP/TIMP expression from human dermal and synovial fibroblasts upon S. aureus treatment. We propose that host-derived MMPs contribute to the progressive joint destruction observed in S. aureus-mediated septic arthritis.