The unfolded protein response mediated by PERK is casually related to the pathogenesis of intervertebral disc degeneration

Takeshi Fujii, Nobuyuki Fujita, Satoshi Suzuki, Takashi Tsuji, Takashi Takaki, Kazuo Umezawa, Kota Watanabe, Takeshi Miyamoto, Keisuke Horiuchi, Morio Matsumoto, Masaya Nakamura

研究成果: Article査読

8 被引用数 (Scopus)

抄録

Although the number of patients with intervertebral disc (IVD) degeneration is increasing in aging societies, its etiology and pathogenesis remain elusive and there is currently no effective treatment to prevent this undesirable condition. The unfolded protein response (UPR) is a cellular machinery that plays critical roles in handling endoplasmic reticulum (ER) stress, a condition caused by the accumulation of unfolded proteins in the ER lumen. This study aimed to elucidate the potential role of the UPR mediated by pancreatic endoplasmic reticulum kinase (PERK), one of the major ER stress sensors in mammalian cells, in the development of IVD degeneration. IVD degeneration was artificially induced in Wister rats by percutaneously puncturing the coccyx IVDs and human IVDs were collected from patients who underwent spinal surgery. Expression of the UPR target genes was elevated in degenerative IVDs in both humans and rats. The induction of ER stress in annulus fibrosus cells significantly increased the transcripts for tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in a nuclear factor (NF)-κB pathway-dependent manner. The expression of TNF-α and IL-6 was significantly reduced by treatment with a selective PERK inhibitor, GSK2606414, and by gene silencing against PERK and activating transcription factor 4 (ATF4) transcripts. Our findings indicate that the UPR mediated by the PERK pathway is causally related to the development of IVD degeneration, suggesting that PERK may be a potential molecular target for suppressing the degenerative changes in IVDs.

本文言語English
ページ(範囲)1334-1345
ページ数12
ジャーナルJournal of Orthopaedic Research
36
5
DOI
出版ステータスPublished - 05-2018

All Science Journal Classification (ASJC) codes

  • Orthopedics and Sports Medicine

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