title: 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.
abstract: 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 RT2profiler 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.
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: doctorfgy@163.com.
authors: Chencheng
authors: C
authors: Feng
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: 65210796@qq.com.
authors: Yang
authors: Y
authors: Zhang
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: doc_ymh@163.com.
authors: Minghui
authors: M
authors: Yang
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: fccdoc@me.com.
authors: Minghong
authors: M
authors: Lan
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: 20016040@163.com.
authors: Huan
authors: H
authors: Liu
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: tonywjxq@aliyun.com.
authors: Jian
authors: J
authors: Wang
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: happyzhou@vip.163.com.
authors: Yue
authors: Y
authors: Zhou
authors: Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: fmmuhb@126.com.
authors: Bo
authors: B
authors: Huang
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D055959:Intervertebral Disc Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D000070614:Nucleus Pulposus / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: C428643:N-acetyl-proline-glycine-proline; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D023062:Receptors, Interleukin-8A; D013879:Thioredoxins; D005978:Glutathione
keywords: Cellular antioxidant system; Disc cell senescence; Homeostasis of intervertebral disc; Intervertebral disc degeneration; Matrikine; N-acetylated proline-glycine-proline