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首页> 外文期刊>Osteoarthritis and cartilage >alpha-MSH inhibits TNF-alpha-induced matrix metalloproteinase-13 expression by modulating p38 kinase and nuclear factor kappaB signaling in human chondrosarcoma HTB-94 cells.
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alpha-MSH inhibits TNF-alpha-induced matrix metalloproteinase-13 expression by modulating p38 kinase and nuclear factor kappaB signaling in human chondrosarcoma HTB-94 cells.

机译：alpha-MSH通过调节人软骨肉瘤HTB-94细胞中的p38激酶和核因子kappaB信号传导来抑制TNF-α诱导的基质金属蛋白酶13表达。

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OBJECTIVE: Proinflammatory cytokine-induced expression of matrix metalloproteinases (MMPs) is a major cause of arthritic cartilage destruction. The neuropeptide, alpha-melanocyte-stimulating hormone (alpha-MSH), has been detected in the synovial fluid of arthritis patients, where it is thought to play an anti-inflammatory role. Here, we examined whether alpha-MSH acts via downregulation of MMP expression, and sought to elucidate the intracellular signal pathways underlying this effect. DESIGN: Human chondrosarcoma cell line, HTB-94 (SW1353) was pretreated with or without alpha-MSH and then treated with tumor necrosis factor-alpha (TNF-alpha). The effect of alpha-MSH on TNF-alpha-induced MMP-13 expression and mitogen-activated protein kinases' (MAPKs) activation were determined by reverse transcriptase-polymerase chain reaction and Western blot analysis. Additionally, the intracellular signaling of alpha-MSH was investigated using the inhibitors of MAPK and nuclear factor kappaB (NF-kappaB) and plasmidsencoding dominant negative (dn) forms of inhibitor kappaB kinase-alpha (IKKalpha) and inhibitor kappaB kinase-beta (IKKbeta). RESULTS: We found that alpha-MSH pretreatment inhibited TNF-alpha-induced MMP-13 expression and p38 kinase phosphorylation in HTB-94 human chondrosarcoma cells. TNF-alpha-induced MMP-13 expression was not suppressed by extracellular signal-regulated kinase (ERK) inhibitors (PD98059 and U0126) or a c-jun terminal kinase (JNK) inhibitor (SP600125), but was inhibited by inhibitors of p38 kinase (SB203580) and NF-kappaB (SN-50 peptide) and dnIKKalpha and dnIKKbeta. CONCLUSIONS: Our results suggest that alpha-MSH regulates TNF-alpha-induced MMP-13 expression by decreasing p38 kinase phosphorylation and subsequent NF-kappaB activation in human chondrocytes and may be an effective inhibitor of MMP-13-mediated collagen degradation, providing new potential opportunities for the development of anti-arthritis therapeutics.
机译：目的：促炎细胞因子诱导的基质金属蛋白酶（MMPs）表达是关节炎软骨破坏的主要原因。在关节炎患者的滑液中已检测到神经肽，即α-黑素细胞刺激激素（α-MSH），据认为在其中起着抗炎作用。在这里，我们检查了α-MSH是否通过下调MMP表达起作用，并试图阐明这种作用的细胞内信号途径。设计：使用或不使用alpha-MSH预处理人软骨肉瘤细胞系HTB-94（SW1353），然后用肿瘤坏死因子α（TNF-alpha）处理。通过逆转录聚合酶链反应和蛋白质印迹分析确定了α-MSH对TNF-α诱导的MMP-13表达和有丝分裂原活化的蛋白激酶（MAPKs）活化的影响。此外，使用MAPK和核因子kappaB（NF-kappaB）抑制剂以及抑制物kappaB激酶-α（IKKalpha）和抑制剂kappaB激酶-beta（IKKbeta ）。结果：我们发现α-MSH预处理抑制了HTB-94人软骨肉瘤细胞中TNF-α诱导的MMP-13表达和p38激酶磷酸化。 TNF-α诱导的MMP-13表达不受细胞外信号调节激酶（ERK）抑制剂（PD98059和U0126）或c-jun末端激酶（JNK）抑制剂（SP600125）抑制，但受p38激酶抑制剂抑制（SB203580）和NF-kappaB（SN-50肽）以及dnIKKalpha和dnIKKbeta。结论：我们的结果表明，α-MSH通过减少人软骨细胞中的p38激酶磷酸化和随后的NF-κB活化来调节TNF-α诱导的MMP-13表达，并且可能是MMP-13介导的胶原降解的有效抑制剂，提供了新的途径。开发抗关节炎疗法的潜在机会。

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