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

Abstract

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.

MEF2C regulates osteoclastogenesis and pathologic bone resorption via c-FOS

“…To address the importance of MEF2C in osteoclast-mediated pathological bone resorption, we tested the effects of MEF2C deficiency on bone loss in K/BXN serum-induced arthritis. 35 K/BxN serum was administrated intra-peritoneally on day 0 and day 2 (Fig. 7a ).…”

Serum Nardilysin, a Surrogate Marker for Epithelial–Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection

“…We recently reported that NRDC levels were increased in the synovial fluid of patients with rheumatoid arthritis (31). NRDC in macrophages regulates arthritis via the control of TNFa secretion because the macrophage-specific deletion of NRDC markedly ameliorated arthritis (31). We also demonstrated that inflammatory cells infiltrating the infarcted myocardium strongly express NRDC (25).…”

“…Another possible source of serum NRDC is inflammatory cells adjacent to tumors. We recently reported that NRDC levels were increased in the synovial fluid of patients with rheumatoid arthritis (31). NRDC in macrophages regulates arthritis via the control of TNFa secretion because the macrophage-specific deletion of NRDC markedly ameliorated arthritis (31).…”

Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor

“…22,23 Moreover, we have recently proposed the possible clinical use of serum NRDC levels as a biomarker for several clinical settings. [24][25][26] For example, serum NRDC is elevated early after the onset in patients with acute coronary syndrome. 27 Here, we demonstrate that NRDC critically regulates circulatory dynamics because Nrdc −/− mice show hypotension and bradycardia.…”

“…In addition to this extracellular function as an enhancer of ectodomain cleavage, NRDC in the nucleus controls transcription as a coregulator of several transcription factors such as peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), 21 islet‐1, 22 and histone deacetylases 23,24 . Moreover, we have recently proposed the possible clinical use of serum NRDC levels as a biomarker for several clinical settings 25‐27 . For example, serum NRDC is elevated early after the onset in patients with acute coronary syndrome 28…”