title: Knockdown of ADAM10 inhibits migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis.
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.
authors.affiliation: Department of Radiology, The First Teaching Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Engineering Mechanics, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Orthopaedics, The Third Teaching Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, The Third Teaching Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors.forename: Xianji
authors.initials: X
authors.lastname: Song
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human