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

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

doi:10.1136/rmdopen-2017-000436

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

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

Authors

Affiliations

¹ Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
³ Department of Pharmacology, Shiga University of Medical Science, Shiga, Japan.
⁴ Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
⁵ Department of Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁶ Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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 (Nrdc^-/- ) mice and macrophage-specific NRDC-deficient (Nrdc^delM ) 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 Nrdc^delM 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.

Keywords: Autoantibodies; Rheumatoid arthritis; Synovial fluid; TNF-alpha.