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

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

3 ( 1 ) 2017-07-01 , BMJ
新たな関節リウマチ治療のターゲット分子としてのナルディライジン. 京都大学プレスリリース. 2017-07-11.
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 (Nrdc–/– ) mice and macrophage-specific NRDC-deficient (NrdcdelM ) 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 Nrdc 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 Nrdc ameliorated CAIA. Results: CAIA and K/BxN STA were significantly attenuated in Nrdc–/– mice and NrdcdelM mice. Gene deletion or silencing of Nrdc 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-Nrdcsmall 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.

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