2. Academic Validation
  3. 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

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

  • Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):220-230. doi: 10.1016/j.bbadis.2016.10.011.
Chencheng Feng 1,  Yang Zhang 2,  Minghui Yang 3,  Minghong Lan 4,  Huan Liu 5,  Jian Wang 6,  Yue Zhou 7,  Bo Huang 8
Affiliations

Affiliations

  • 1 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: doctorfgy@163.com.
  • 2 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: 65210796@qq.com.
  • 3 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: doc_ymh@163.com.
  • 4 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: fccdoc@me.com.
  • 5 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: 20016040@163.com.
  • 6 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: tonywjxq@aliyun.com.
  • 7 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: happyzhou@vip.163.com.
  • 8 Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: fmmuhb@126.com.
PMID: 27769935 DOI: 10.1016/j.bbadis.2016.10.011
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 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.

Keywords

Cellular antioxidant system; Disc cell senescence; Homeostasis of intervertebral disc; Intervertebral disc degeneration; Matrikine; N-acetylated proline-glycine-proline.

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