Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis
Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis
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DOI：
10.1002/art.27476
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发表时间：
2010-07-01
影响因子：
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通讯作者：
Rowan, Andrew D.
中科院分区：
文献类型：
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作者：
Milner, Jennifer M.;Patel, Amit;Rowan, Andrew D.
目标。越来越多的证据表明丝氨酸蛋白酶与病理性组织周转有关。本研究的目的是评估跨膜型丝氨酸蛋白酶在骨关节炎(OA)软骨破坏中的作用。用低密度芯片检测髋关节骨性关节炎患者和股骨颈骨折患者股骨头软骨中丝氨酸蛋白酶基因的表达。在软骨降解模型上检测Mattritase对胶原降解的影响，并用实时定量聚合酶链式反应分析其对基质金属蛋白酶(MMPs)表达的影响。用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳法和N-末端测序法测定前基质金属蛋白酶的加工，并用滑膜灌注法测定其激活蛋白酶激活受体2(PAR-2)的能力。与NOF软骨相比，在OA软骨中Mattritase基因的表达显著增加，并且Mattritase免疫定位于OA软骨细胞。我们发现，Mattritase激活了proMMP1，并将proMMP3加工成完全活性的形式。外源性Mattritase显著促进细胞因子刺激的软骨胶原酶分解，而Mattritase单独作用能显著促进依赖于金属蛋白酶的OA软骨的胶原酶分解。Mattritase还可诱导MMP1、MMP3和MMP13基因的表达。滑膜血流灌注数据证实，Mattritase激活了PAR-2，并且我们证明了PAR-2的抑制阻断了Mattritase依赖的促进骨性关节炎软骨胶原分解的作用。该丝氨酸蛋白酶在骨性关节炎中的高表达以及激活选择性原MMPs和诱导胶原酶表达的能力使其成为骨性关节炎软骨破坏的关键启动者和诱导者。我们认为，Mattritase的间接作用是由PAR-2介导的，对这些机制的更详细的了解可能会为OA的治疗提供重要的新的治疗靶点。
Objective. Increasing evidence implicates serine proteinases in pathologic tissue turnover. The aim of this study was to assess the role of the transmembrane serine proteinase matriptase in cartilage destruction in osteoarthritis (OA).Methods. Serine proteinase gene expression in femoral head cartilage obtained from either patients with hip OA or patients with fracture to the neck of the femur (NOF) was assessed using a low-density array. The effect of matriptase on collagen breakdown was determined in cartilage degradation models, while the effect on matrix metalloproteinase (MMP) expression was analyzed by real-time polymerase chain reaction. ProMMP processing was determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis/N-terminal sequencing, while its ability to activate proteinase-activated receptor 2 (PAR-2) was determined using a synovial perfusion assay in mice.Results. Matriptase gene expression was significantly elevated in OA cartilage compared with NOF cartilage, and matriptase was immunolocalized to OA chondrocytes. We showed that matriptase activated proMMP-1 and processed proMMP-3 to its fully active form. Exogenous matriptase significantly enhanced cytokine-stimulated cartilage collagenolysis, while matriptase alone caused significant collagenolysis from OA cartilage, which was metalloproteinase-dependent. Matriptase also induced MMP-1, MMP-3, and MMP-13 gene expression. Synovial perfusion data confirmed that matriptase activates PAR-2, and we demonstrated that matriptase-dependent enhancement of collagenolysis from OA cartilage is blocked by PAR-2 inhibition.Conclusion. Elevated matriptase expression in OA and the ability of matriptase to activate selective proMMPs as well as induce collagenase expression make this serine proteinase a key initiator and inducer of cartilage destruction in OA. We propose that the indirect effects of matriptase are mediated by PAR-2, and a more detailed understanding of these mechanisms may highlight important new therapeutic targets for OA treatment.