基质金属蛋白酶 13 被中性粒细胞弹性蛋白酶完全激活并使其丝氨酸蛋白酶抑制剂 α-1 抗胰蛋白酶失活：对骨关节炎的影响,The FEBS Journal

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基质金属蛋白酶 13 被中性粒细胞弹性蛋白酶完全激活并使其丝氨酸蛋白酶抑制剂 α-1 抗胰蛋白酶失活：对骨关节炎的影响
The FEBS Journal ( IF 5.5 ) Pub Date : 2021-07-16 , DOI: 10.1111/febs.16127
David J. Wilkinson _{1,

2} , Adrian M. D. Falconer ₂ , Helen L. Wright ₁ , Hua Lin ₂ , Kazuhiro Yamamoto ₁ , Kathleen Cheung ₂ , Sarah H. Charlton ₂ , Maria del Carmen Arques ₂ , Sabina Janciauskiene ₃ , Ramsay Refaie ₂ , Kenneth S. Rankin ₄ , David A. Young ₂ , Andrew D. Rowan ₂

Affiliation

基质金属蛋白酶 13 (MMP-13) 是一种独特重要的胶原酶，可促进骨关节炎 (OA) 中软骨胶原的不可逆破坏。胶原酶激活是发生软骨分解的关键控制点，但我们对参与该过程的蛋白酶的了解是有限的。中性粒细胞弹性蛋白酶 (NE) 是一种广为人知的蛋白多糖降解酶，历史上与炎症性关节炎有关，但最近的证据表明其在 OA 中具有潜在作用。在这项研究中，我们研究了中性粒细胞弹性蛋白酶对 OA 软骨胶原蛋白破坏和胶原酶激活的影响。中性粒细胞弹性蛋白酶以 MMP 依赖性方式从体外诱导人 OA 软骨中的显着胶原蛋白破坏。体外，中性粒细胞弹性蛋白酶直接和强烈激活 pro-MMP-13，N 端测序鉴定了靠近⁷² MKKPR半胱氨酸开关的切割，最终导致具有⁸⁵ YNVFP的新 N 端的完全活性形式。每摩尔摩尔的激活比 MMP-3（一种经典的胶原酶激活剂）更有效。在人类 OA 滑液和 OA 滑膜中可检测到弹性蛋白酶，其显示出滑膜炎的组织学分级证据。生物信息学分析表明，与其他组织相比，对照软骨的主要弹性蛋白酶抑制剂 (AAT) α-1 抗胰蛋白酶（基因名称SERPINA1)，但这些在 OA 中减少了。AAT 主要位于浅表软骨区，并且在软骨损伤区域染色增强。最后，活性 MMP-13 通过去除丝氨酸蛋白酶切割/抑制位点来特异性地灭活 AAT。总之，这项研究将弹性蛋白酶确定为 pro-MMP-13 的一种新型激活剂，它与患有滑膜炎的 OA 患者的软骨胶原蛋白破坏有关。

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Matrix metalloproteinase-13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis

Matrix metalloproteinase-13 (MMP-13) is a uniquely important collagenase that promotes the irreversible destruction of cartilage collagen in osteoarthritis (OA). Collagenase activation is a key control point for cartilage breakdown to occur, yet our understanding of the proteinases involved in this process is limited. Neutrophil elastase (NE) is a well-described proteoglycan-degrading enzyme which is historically associated with inflammatory arthritis, but more recent evidence suggests a potential role in OA. In this study, we investigated the effect of neutrophil elastase on OA cartilage collagen destruction and collagenase activation. Neutrophil elastase induced significant collagen destruction from human OA cartilage ex vivo, in an MMP-dependent manner. In vitro, neutrophil elastase directly and robustly activated pro-MMP-13, and N-terminal sequencing identified cleavage close to the cysteine switch at ⁷²MKKPR, ultimately resulting in the fully active form with the neo-N terminus of ⁸⁵YNVFP. Mole-per-mole, activation was more potent than by MMP-3, a classical collagenase activator. Elastase was detectable in human OA synovial fluid and OA synovia which displayed histologically graded evidence of synovitis. Bioinformatic analyses demonstrated that, compared with other tissues, control cartilage exhibited remarkably high transcript levels of the major elastase inhibitor, (AAT) alpha-1 antitrypsin (gene name SERPINA1), but these were reduced in OA. AAT was located predominantly in superficial cartilage zones, and staining enhanced in regions of cartilage damage. Finally, active MMP-13 specifically inactivated AAT by removal of the serine proteinase cleavage/inhibition site. Taken together, this study identifies elastase as a novel activator of pro-MMP-13 that has relevance for cartilage collagen destruction in OA patients with synovitis.

更新日期：2021-07-16

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