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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1334-1345
Number of pages12
JournalJournal of Orthopaedic Research
Volume36
Issue number5
DOIs
Publication statusPublished - 01-05-2018

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Unfolded Protein Response
Intervertebral Disc Degeneration
Endoplasmic Reticulum
Phosphotransferases
Endoplasmic Reticulum Stress
Interleukin-6
Activating Transcription Factor 4
Coccyx
Tumor Necrosis Factor-alpha
Protein Unfolding
Gene Silencing
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Orthopedics and Sports Medicine

Cite this

Fujii, Takeshi ; Fujita, Nobuyuki ; Suzuki, Satoshi ; Tsuji, Takashi ; Takaki, Takashi ; Umezawa, Kazuo ; Watanabe, Kota ; Miyamoto, Takeshi ; Horiuchi, Keisuke ; Matsumoto, Morio ; Nakamura, Masaya. / The unfolded protein response mediated by PERK is casually related to the pathogenesis of intervertebral disc degeneration. In: Journal of Orthopaedic Research. 2018 ; Vol. 36, No. 5. pp. 1334-1345.
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Fujii, T, Fujita, N, Suzuki, S, Tsuji, T, Takaki, T, Umezawa, K, Watanabe, K, Miyamoto, T, Horiuchi, K, Matsumoto, M & Nakamura, M 2018, 'The unfolded protein response mediated by PERK is casually related to the pathogenesis of intervertebral disc degeneration', Journal of Orthopaedic Research, vol. 36, no. 5, pp. 1334-1345. https://doi.org/10.1002/jor.23787

The unfolded protein response mediated by PERK is casually related to the pathogenesis of intervertebral disc degeneration. / Fujii, Takeshi; Fujita, Nobuyuki; Suzuki, Satoshi; Tsuji, Takashi; Takaki, Takashi; Umezawa, Kazuo; Watanabe, Kota; Miyamoto, Takeshi; Horiuchi, Keisuke; Matsumoto, Morio; Nakamura, Masaya.

In: Journal of Orthopaedic Research, Vol. 36, No. 5, 01.05.2018, p. 1334-1345.

Research output: Contribution to journalArticle

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T1 - The unfolded protein response mediated by PERK is casually related to the pathogenesis of intervertebral disc degeneration

AU - Fujii, Takeshi

AU - Fujita, Nobuyuki

AU - Suzuki, Satoshi

AU - Tsuji, Takashi

AU - Takaki, Takashi

AU - Umezawa, Kazuo

AU - Watanabe, Kota

AU - Miyamoto, Takeshi

AU - Horiuchi, Keisuke

AU - Matsumoto, Morio

AU - Nakamura, Masaya

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Y1 - 2018/5/1

N2 - 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.

AB - 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.

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