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

ObjectiveTumour 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 s...

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Published in:Rheumatic & musculoskeletal diseases open 2017-07, Vol.3 (1), p.e000436-e000436
Main Authors: 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
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animal Models
Ankle
Chemokines
Collagen
Cytokines
Epidermal growth factor
Joint surgery
Pathogenesis
Proteins
Rheumatoid arthritis
Rodents
TNF inhibitors
Tumor necrosis factor-TNF
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Summary:ObjectiveTumour 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.MethodsNRDC-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.ResultsCAIA 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.ConclusionThese data indicate that NRDC plays crucial roles in the pathogenesis of autoimmune arthritis and could be a new therapeutic target for RA treatment.
ISSN:2056-5933
2056-5933
DOI:10.1136/rmdopen-2017-000436