title: Recombinant human endostatin inhibits TNF-alpha-induced receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes in mice with adjuvant arthritis.
abstract: Bone loss is a critical pathology responsible for the functional disability in patients with rheumatoid arthritis (RA). It is well known that receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) plays a crucial role in bone loss in RA. The purpose of this study was to determine whether recombinant human endostatin (rh-endostatin) mediates bone erosion in RA by regulation of RANKL expression in an experimental model of RA, consisting of mice with adjuvant-induced arthritis (AA). Cultured AA fibroblast-like synoviocytes (FLSs) obtained from these mice were induced by tumor necrosis factor-α (TNF-α) combined with or without rh-endostatin. The levels of RANKL and osteoprotegerin (OPG) mRNA, soluble and membrane-bound proteins were assessed by real-time PCR, ELISA, and Western blotting. Western blotting and the luciferase reporter assay were used to study related signaling pathways. Rh-endostatin inhibited RANKL mRNA expression, soluble and membrane-bound protein expression in AA FLSs but not in CD4+ T cells. However, OPG expression and secretion was not affected by rh-endostatin in AA FLSs. Molecular analysis demonstrated that rh-endostatin significantly inhibited TNF-α-induced MAPK and AP-1 signaling pathways. Moreover, rh-endostatin attenuated TNF-α-induced NF-κB signaling by suppressing the phosphorylation level of inhibitor kappaBα (IκBα) and nuclear translocation of NF-κB p65 in FLSs from mice with AA. These results provide the first evidence that rh-endostatin inhibits TNF-α-induced RANKL expression in AA FLSs.
authors.affiliation: Department of Pharmacy, The Third Hospital Affiliated to Nantong University, Wuxi, Jiangsu, 214041, China.
authors.forename: Qiu-Fang
authors.initials: QF
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214041, China.
authors.forename: Xiu-Hong
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics and Central Laboratory, The Third Hospital Affiliated to Nantong University, Wuxi, Jiangsu, 214041, China.
authors.forename: Feng-Lai
authors.initials: FL
authors.lastname: Yuan
authors.affiliation: Department of Orthopaedics, Jinshan Hospital, Fudan University, Shanghai, 201508, China.
authors.forename: Ming-Dong
authors.initials: MD
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, The Third Hospital Affiliated to Nantong University, Wuxi, Jiangsu, 214041, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D043169:Endostatins / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D053244:Osteoprotegerin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D000070918:Synoviocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D043169:Endostatins; D020672:I-kappa B Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha
keywords: IκBα; NF-κB; bone destruction; fibroblast-like synoviocytes; rheumatoid arthritis