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nardilysin通过调节肿瘤坏死因子α的分泌参与自身免疫性关节炎。

Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion.

作者信息

Fujii Takayuki, Nishi Eiichiro, Ito Hiromu, Yoshitomi Hiroyuki, Furu Moritoshi, Okabe Namiko, Ohno Mikiko, Nishi Kiyoto, Morita Yusuke, Morita Yugo, Azukizawa Masayuki, Okahata Akinori, Tomizawa Takuya, Kimura Takeshi, Matsuda Shuichi

机构信息

Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

出版信息

RMD Open. 2017 Jul 13;3(1):e000436. doi: 10.1136/rmdopen-2017-000436. eCollection 2017.

DOI:10.1136/rmdopen-2017-000436
PMID:28955486
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5604610/
Abstract

OBJECTIVE

Tumour necrosis factor alpha (TNF-α) plays an important role in rheumatoid arthritis (RA). TNF-α is synthesised as a membrane-anchored precursor and is fully activated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated ectodomain shedding. Nardilysin (NRDC) facilitates ectodomain shedding via activation of ADAM17. This study was undertaken to elucidate the role of NRDC in RA.

METHODS

NRDC-deficient ( ) mice and macrophage-specific NRDC-deficient ( ) mice were examined in murine RA models, collagen antibody-induced arthritis (CAIA) and K/BxN serum transfer arthritis (K/BxN STA). We evaluated the effect of gene deletion or silencing of on ectodomain shedding of TNF-α in macrophages or monocytes. NRDC concentration in synovial fluid from patients with RA and osteoarthritis (OA) were measured. We also examined whether local gene silencing of ameliorated CAIA.

RESULTS

CAIA and K/BxN STA were significantly attenuated in mice and mice. Gene deletion or silencing of in macrophages or THP-1 cells resulted in the reduction of TNF-α shedding. The level of NRDC is higher in synovial fluid from RA patients compared with that from OA patients. Intra-articular injection of anti-small interfering RNA ameliorated CAIA.

CONCLUSION

These data indicate that NRDC plays crucial roles in the pathogenesis of autoimmune arthritis and could be a new therapeutic target for RA treatment.

摘要

目的

肿瘤坏死因子α（TNF-α）在类风湿关节炎（RA）中起重要作用。TNF-α作为膜锚定前体合成，并通过解整合素和金属蛋白酶17（ADAM17）介导的胞外域脱落而被完全激活。Nardilysin（NRDC）通过激活ADAM17促进胞外域脱落。本研究旨在阐明NRDC在RA中的作用。

方法

在小鼠RA模型、胶原抗体诱导的关节炎（CAIA）和K/BxN血清转移关节炎（K/BxN STA）中检测NRDC缺陷（ ）小鼠和巨噬细胞特异性NRDC缺陷（ ）小鼠。我们评估了基因缺失或沉默 对巨噬细胞或单核细胞中TNF-α胞外域脱落的影响。测量了RA患者和骨关节炎（OA）患者滑液中的NRDC浓度。我们还研究了 的局部基因沉默是否改善了CAIA。

结果

小鼠和 小鼠的CAIA和K/BxN STA均显著减轻。巨噬细胞或THP-1细胞中 的基因缺失或沉默导致TNF-α脱落减少。与OA患者相比，RA患者滑液中NRDC水平更高。关节内注射抗小干扰RNA改善了CAIA。

结论

这些数据表明NRDC在自身免疫性关节炎的发病机制中起关键作用，可能是RA治疗的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/fe191d7e0cef/rmdopen-2017-000436f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/3e5e08fa3bd2/rmdopen-2017-000436f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/b17f58b2fa9e/rmdopen-2017-000436f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/a60fe9c14934/rmdopen-2017-000436f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/41d2a2663c00/rmdopen-2017-000436f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/fe191d7e0cef/rmdopen-2017-000436f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/3e5e08fa3bd2/rmdopen-2017-000436f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/b17f58b2fa9e/rmdopen-2017-000436f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/a60fe9c14934/rmdopen-2017-000436f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/41d2a2663c00/rmdopen-2017-000436f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7291/5604610/fe191d7e0cef/rmdopen-2017-000436f05.jpg

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