title: A combination of sinomenine and methotrexate reduces joint damage of collagen induced arthritis in rats by modulating osteoclast-related cytokines.
abstract: OBJECTIVE
  To analyze the combination therapy of Sinomenine (SIN) and Methotrexate (MTX) in rheumatoid arthritis (RA), we herein demonstrated the combination effect of SIN and MTX on collagen-induced arthritis (CIA) in rats through their modulation on osteoclast-related cytokines.
  
  
  METHODS
  CIA was induced by the immunization of type II collagen (CII) in SD rats. SIN and MTX were administrated alone or in combination after the onset of arthritis. Arthritis index and histological analysis were used to evaluate the effect of treatments. Effects of SIN and MTX on expression of receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) in synovial tissues were assayed by immunohistochemistry. RANKL, osteoprotegerin (OPG), IL-6, IL-17 and matrix metalloproteinases (MMPs) in rat serum were measured by ELISA. The expression of osteoclast-related cytokines in fibroblast-like synoviocytes (FLS) from RA patients was assayed by RT-PCR.
  
  
  RESULTS
  SIN and MTX combination additively reduced the inflammatory symptoms and joint damage in CIA. Combination of SIN and MTX significantly repressed synovial RANKL and OPN production. SIN and MTX exhibited complementary and synergistic effect upon down-regulating RANKL, IL-6, IL-17 and MMPs in rat serum. SIN and MTX also modulated the expression of RANKL and OPG in RA-FLS.
  
  
  CONCLUSIONS
  SIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321#, 210008 Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321#, 210008 Nanjing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321#, 210008 Nanjing, China. Electronic address: dingcongzhu@163.com.
authors.forename: Cong-zhu
authors.initials: CZ
authors.lastname: Ding
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage*; D009019:Morphinans / Q000008:administration & dosage*; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D024043:Collagen Type II; D016207:Cytokines; D009019:Morphinans; D053245:RANK Ligand; D053495:Osteopontin; C009271:sinomenine; D008727:Methotrexate
keywords: Collagen induced arthritis; Fibroblast-like synoviocytes; Methotrexate; Osteoclasts; Sinomenine