SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways.
SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways.
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DOI：
10.1371/journal.pone.0135979
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gualillo O
中科院分区：
文献类型：
--
作者：
Santoro A;Conde J;Scotece M;Abella V;Lois A;Lopez V;Pino J;Gomez R;Gomez-Reino JJ;Gualillo O
骨关节炎（OA）是一种慢性关节疾病，其特征在于关节软骨的进行性丧失。在OA过程中，促炎细胞因子，如白细胞介素IL-1，诱导软骨细胞中基质金属蛋白酶（MMPs）的表达，从而促进细胞外基质（ECM）降解。丝氨酸蛋白酶家族成员，包括纤溶酶原激活物抑制剂，已被报道参与ECM调节。本研究的目的是评估在基础条件下以及对IL-1α剂量增加的响应下，丝氨酸蛋白酶抑制剂肽酶抑制剂进化枝E成员2（SERPINE 2）在人培养软骨细胞中的表达。我们还检测了SERPINE 2对IL-1α诱导的MMP-13表达的影响。为了完整性，还探索了参与该过程的信号通路。通过RT-qPCR和蛋白质印迹分析评估人T/C-28 a2细胞系和人原代软骨细胞中的SERPINE 2 mRNA和蛋白质表达。用人重组SERPINE 2单独或与IL-1α联合处理这些细胞。Western blot法检测ERK 1/2、NFκB B和AP-1活性。人培养的软骨细胞在基础条件下表达SERPINE 2。这种表达在对IL-1α刺激的反应中增加。此外，重组SERPINE 2诱导明显抑制IL-1α刺激的软骨细胞中MMP-13的表达。这种抑制作用可能通过ERK 1/2、NF-κB和AP-1通路调节。总之，这些数据表明SERPINE 2可能通过抑制MMP-13的表达来预防软骨软骨炎，MMP-13是最相关的胶原酶之一，参与OA中的软骨分解。
Osteoarthritis (OA) is a chronic joint disease, characterized by a progressive loss of articular cartilage. During OA, proinflammatory cytokines, such as interleukin IL-1, induce the expression of matrix metalloproteinases (MMPs) in chondrocytes, contributing thus to the extracellular matrix (ECM) degradation. Members of Serpine family, including plasminogen activator inhibitors have been reported to participate in ECM regulation. The aim of this study was to assess the expression of serpin peptidase inhibitor clade E member 2 (SERPINE2), under basal conditions and in response to increasing doses of IL-1α, in human cultured chondrocytes. We also examined the effects of SERPINE2 on IL-1α-induced MMP-13 expression. For completeness, the signaling pathway involved in this process was also explored. SERPINE2 mRNA and protein expression were evaluated by RT-qPCR and western blot analysis in human T/C-28a2 cell line and human primary chondrocytes. These cells were treated with human recombinant SERPINE2, alone or in combination with IL-1α. ERK 1/2, NFκB and AP-1 activation were assessed by western blot analysis. Human cultured chondrocytes express SERPINE2 in basal condition. This expression increased in response to IL-1α stimulation. In addition, recombinant SERPINE2 induced a clear inhibition of MMP-13 expression in IL-1α-stimulated chondrocytes. This inhibitory effect is likely regulated through a pathway involving ERK 1/2, NF-κB and AP-1. Taken together, these data demonstrate that SERPINE2 might prevent cartilage catabolism by inhibiting the expression of MMP-13, one of the most relevant collagenases, involved in cartilage breakdown in OA.