Pinealectomy in vertebrates accelerated intervertebral disk degeneration (IDD). However, the potential mechanisms, particularly melatonin's role, are still to be clarified. In this study, for first time, melatonin membrane receptors of MT1 and MT2 were found to be present in the human intervertebral disk tissues and nucleus pulposus (NP) cells, respectively. Melatonin treatment significantly inhibited NP cell proliferation in dose‐dependent manner. Accordingly, melatonin down‐regulated gene expression of cyclin D1, PCNA, matrix metallopeptidase‐3, and matrix metallopeptidase‐9 and upregulated gene expression of collagen type II alpha 1 chain and aggrecan in NP cells. These effects of melatonin were blocked by luzindole, a nonspecific melatonin membrane receptor antagonist. Signaling pathway analysis indicated that in the intervertebral disk tissues and NP cells, melatonin acted on MT1/2 and subsequently reduced phosphorylation of phosphoinositide 3‐kinase p85 regulatory subunit, phosphoinositide‐dependent kinase‐1, and Akt. The results indicate that melatonin is a crucial regulator of NP cell function and plays a vital role in prevention of IDD.

中文翻译：

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褪黑素通过褪黑素膜受体介导的PI3K‐Akt途径抑制髓核（NP）细胞增殖和细胞外基质（ECM）重塑

脊椎动物中的松果体切除术加速了椎间盘退变（IDD）。但是，潜在的机制，尤其是褪黑激素的作用，仍需进一步阐明。在这项研究中，首次发现人椎间盘组织和髓核（NP）细胞中分别存在MT1和MT2的褪黑素膜受体。褪黑素治疗以剂量依赖性方式显着抑制NP细胞增殖。因此，褪黑激素下调了NP细胞中cyclin D1，PCNA，基质金属肽酶-3和基质金属肽酶-9的基因表达，并上调了II型胶原α1链和聚集蛋白聚糖的基因表达。褪黑激素的这些作用被Luzindole（一种非特异性的褪黑激素膜受体拮抗剂）阻断。信号通路分析表明，在椎间盘组织和NP细胞中，褪黑激素作用于MT1 / 2，随后减少了磷酸肌醇3激酶p85调节亚基，磷酸肌醇依赖性激酶-1和Akt的磷酸化。结果表明，褪黑激素是NP细胞功能的关键调节剂，在预防IDD中起着至关重要的作用。