Fujii Takeshi, Fujita Nobuyuki, Suzuki Satoshi, Tsuji Takashi, Takaki Takashi, Umezawa Kazuo, Watanabe Kota, Miyamoto Takeshi, Horiuchi Keisuke, Matsumoto Morio, Nakamura Masaya
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan.
Department of Orthopaedic Surgery, Fujita Health University, Aichi, Japan.
J Orthop Res. 2018 May;36(5):1334-1345. doi: 10.1002/jor.23787. Epub 2017 Nov 28.
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. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1334-1345, 2018.
尽管在老龄化社会中，椎间盘（IVD）退变患者的数量在不断增加，但其病因和发病机制仍不清楚，目前尚无有效的治疗方法来预防这种不良状况。未折叠蛋白反应（UPR）是一种细胞机制，在处理内质网（ER）应激中发挥关键作用，内质网应激是由未折叠蛋白在内质网腔中积累引起的一种状况。本研究旨在阐明由胰腺内质网激酶（PERK）介导的UPR在IVD退变发展中的潜在作用，PERK是哺乳动物细胞中主要的内质网应激传感器之一。通过经皮穿刺尾骨IVD在Wister大鼠中人工诱导IVD退变，并从接受脊柱手术的患者中收集人IVD。UPR靶基因的表达在人和大鼠的退变IVD中均升高。纤维环细胞中内质网应激的诱导以核因子（NF）-κB途径依赖的方式显著增加了肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）的转录本。用选择性PERK抑制剂GSK2606414处理以及针对PERK和激活转录因子4（ATF4）转录本的基因沉默显著降低了TNF-α和IL-6的表达。我们的研究结果表明，由PERK途径介导的UPR与IVD退变的发展存在因果关系，这表明PERK可能是抑制IVD退变变化的潜在分子靶点。©2017骨科研究协会。由Wiley Periodicals, Inc.出版。《矫形外科学研究》36:1334 - 1345，2018年。
