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首页> 外文期刊>Osteoarthritis and cartilage >MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation--divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation.
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MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation--divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation.

机译：MAPKs是蛋白水解软骨降解中必不可少的上游信号传导途径-导致聚集蛋白聚糖酶和MMP介导的关节软骨降解的途径存在差异。

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OBJECTIVES: Matrix metalloproteinases (MMPs) and aggrecanases are essential players in cartilage degradation. However, the signaling pathways that results in MMP and/or aggrecanase synthesis and activation are not well understood. We investigated the molecular events leading to MMP- and aggrecanase-mediated cartilage degradation. METHODS: Cartilage degradation was induced in bovine articular cartilage explants by oncostatin M (OSM) and tumor necrosis factor (TNF), in the presence or absence of specific inhibitors of the mitogen-activated protein kinases (MAPKs) P38, P44/42 and Src family. Toxicity was followed by the AlamarBlue colorimetric assay. MMP-activity was assessed using a fluorescent substrate assay and MMP-9 and -2 activities by gelatinase zymography. MMP-mediated collagen type II degradation and MMP as well as aggrecanase-mediated aggrecan degradation was investigated with specific ELISA and hydroxyproline release by standard methods. The findings were verified by immunohistochemistry and histology. RESULTS: Stimulation of cartilage degradation by OSM+TNF resulted in 100-fold induction of CTX-II release (P<0.01). This was dose-dependently inhibited by MAPK P38 inhibitors and by the MAPK P44/42 inhibitors. MMP-activity and expression was significantly decreased, as evaluated by cleavage of fluorescence MMP-substrate and zymography. Immunohistochemistry confirmed these findings. Interestingly, only the P44/42 inhibitors abrogated aggrecanase-mediated aggrecan degradation. CONCLUSION: We found that inhibition of MAPK P38, P44/42 and Src family abrogated proteolytic cartilage degradation by blocking MMP synthesis and activity. However, only MAPK P44/42 was essential for aggrecanase-mediated aggrecan degradation. These data suggest that various aspects of cartilage degradation can be targeted independently by inhibiting specific upstream signaling pathway.
机译：目的：基质金属蛋白酶（MMPs）和软骨聚集蛋白聚糖酶是软骨降解的重要参与者。然而，导致MMP和/或软骨聚集蛋白聚糖酶合成和活化的信号传导途径尚未被很好地理解。我们调查了导致MMP和软骨聚集蛋白聚糖酶介导的软骨降解的分子事件。方法：在存在或不存在促分裂原激活蛋白激酶（MAPK）P38，P44 / 42和Src特异性抑制剂的情况下，抑瘤素M（OSM）和肿瘤坏死因子（TNF）诱导牛关节软骨外植体发生软骨降解。家庭。毒性之后进行AlamarBlue比色测定。使用荧光底物测定评估MMP活性，并通过明胶酶酶谱法评估MMP-9和-2活性。 MMP介导的II型胶原降解和MMP以及软骨聚集蛋白聚糖酶介导的软骨聚集蛋白降解均采用标准方法通过特异性ELISA和羟脯氨酸释放进行了研究。免疫组织化学和组织学证实了该发现。结果：OSM + TNF刺激软骨降解导致CTX-II释放100倍诱导（P <0.01）。它被MAPK P38抑制剂和MAPK P44 / 42抑制剂剂量依赖性地抑制。通过切割荧光MMP底物和酶谱评估，MMP活性和表达显着降低。免疫组织化学证实了这些发现。有趣的是，仅P44 / 42抑制剂消除了软骨聚集蛋白聚糖酶介导的软骨聚集蛋白聚糖降解。结论：我们发现抑制MAPK P38，P44 / 42和Src家族通过阻止MMP的合成和活性消除了蛋白水解软骨的降解。但是，只有MAPK P44 / 42对蛋白聚糖酶介导的蛋白聚糖的降解是必需的。这些数据表明，可以通过抑制特定的上游信号传导途径独立地靶向软骨降解的各个方面。

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