The matrikine N-acetylated proline-glycine-proline induces premature senescence of nucleus pulposus cells via CXCR1-dependent ROS accumulation and DNA damage and reinforces the destructive effect of these cells on homeostasis of intervertebral discs

Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac-PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1. N-Ac-PGP induced DNA damage and reactive oxygen species accumulation in NP cells, which resulted in activation of the p53-p21-Rb and p16-Rb pathways. Moreover, the RT2 profiler PCR array showed that N-Ac-PGP down regulates the expression of antioxidant genes in NP cells, suggesting a decline in the antioxidants of NP cells. On the other hand, N-Ac-PGP up-regulated the expression of matrix catabolic genes and inflammatory genes in NP cells. Concomitantly, N-Ac-PGP reinforced the destructive effects of senescent NP cells on the homeostasis of the IVDs in vivo. Our study suggests that N-Ac-PGP plays critical roles in the pathogenesis of IDD through the induction of premature senescence of disc cells and via the activation of catabolic and inflammatory cascades in disc cells. N-Ac-PGP also deteriorates the redox environment of disc cells. Hence, N-Ac-PGP is a new potential therapeutic target for IDD. (C) 2016 The Authors. Published by Elsevier B.V.

椎间盘（IVD）细胞衰老被认为是椎间盘退变（IDD）的一种机制。阐明椎间盘细胞衰老的分子机制将有助于理解IDD的发病机制。我们先前报道过，一种基质因子N - 乙酰化脯氨酸 - 甘氨酸 - 脯氨酸（N - Ac - PGP）参与了IDD的过程。然而，其在IDD中的作用尚未完全明确。在此，我们利用大鼠髓核（NP）细胞发现，N - Ac - PGP通过与CXCR1结合诱导NP细胞过早衰老。N - Ac - PGP诱导NP细胞的DNA损伤和活性氧积累，从而导致p53 - p21 - Rb和p16 - Rb通路的激活。此外，RT2 Profiler PCR芯片显示N - Ac - PGP下调NP细胞中抗氧化基因的表达，这表明NP细胞的抗氧化能力下降。另一方面，N - Ac - PGP上调NP细胞中基质分解代谢基因和炎症基因的表达。同时，N - Ac - PGP增强了衰老的NP细胞在体内对椎间盘内稳态的破坏作用。我们的研究表明，N - Ac - PGP通过诱导椎间盘细胞过早衰老以及激活椎间盘细胞中的分解代谢和炎症级联反应，在IDD的发病机制中起关键作用。N - Ac - PGP还恶化了椎间盘细胞的氧化还原环境。因此，N - Ac - PGP是IDD的一个新的潜在治疗靶点。（C）2016作者。由爱思唯尔出版集团出版。