ADAM-10をノックダウンすると関節リウマチFLSのmigrationやinvasionが抑制される【Journal Club 20181121】

Knockdown of ADAM10 inhibits migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis

DAN LI1, ZHITAO XIAO2, GANG WANG3 and XIANJI SONG3

2015 Oct;12(4):5517-23.

Abstract. Rheumatoid arthritis (RA) is a systemic autoim­mune disease with high rates of morbidity and mortality. Previous studies proposed that the A disintegrin and metal­loprotease (ADAM) family is involved in the regulation of inflammation and arthritis. Thus, the present study inves­tigated whether ADAM10 is involved in the progression of RA. The effects of ADAM10 small interfering (si)RNA on the expression levels of tumor necrosis factor (TNF)‑α, inter­leukin (IL)‑6, IL‑8 and chemokine (C-X-C motif) ligand 16 (CXCL16) were determined in fibroblast‑like synoviocytes (FLS). In addition, the effects of ADAM10 siRNA on cell proliferation, invasion and migration in human RA‑FLS were assessed in vitro. The therapeutic efficacy and side‑effects of ADAM10 siRNA were examined in a mouse model of collagen‑induced arthritis (CIA). In vitro, ADAM10 silencing suppressed the expression of TNF‑α, IL‑6, IL‑8 and CXCL16 in lipopolysaccharide (LPS)‑stimulated human RA‑FLS. LPS‑induced RA‑FLS proliferation, migration and invasion were significantly attenuated by ADAM10 knockdown. ADAM10 silencing inhibited the secretion of vascular endothelial growth factor A (VEGF‑A) and matrix metalloproteinase (MMP)‑3 and ‑9 from LPS‑stim­ulated human RA‑FLS, in addition to inhibiting the phos­phoinositide 3‑kinase/AKT activation in LPS‑stimulated human RA‑FLS. In vivo, treatment with siRNA against ADAM10 for three weeks reduced the arthritis score. Serum levels of VEGF‑A, MMP‑3 and MMP‑9 were also reduced in CIA mice. These observations indicate that the inhibi­tion of ADAM10 may be a viable therapeutic target in the amelioration of disease progression in RA by attenuating FLS proliferation, migration and invasion.

関節リウマチFLSにおいて、siRNA法を用いてADAM-10をノックダウンしFLSmigrationinvasionproliferationを検討した。ADAM-10ノックダウンするといずれも抑制された。またADAM-10siRNAで処理した関節炎マウスの関節炎は改善した。以上からADAM-10が関節リウマチの滑膜炎に関与している可能性が示唆された。

 

担当:古屋秀和

 

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