title: Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE(2), and MMP-13 expression.
abstract: OBJECTIVE
  To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms.
  
  
  METHODS
  AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR.
  
  
  RESULTS
  In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE2, and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins.
  
  
  CONCLUSIONS
  NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE2, and MMP-13 expression via the p38/ERK/AKT/AP-1 pathway.
authors: State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors: Zhi-feng
authors: ZF
authors: Wei
authors: Xiao-lan
authors: XL
authors: Jiao
authors: Ting
authors: T
authors: Wang
authors: Qian
authors: Q
authors: Lu
authors: Yu-feng
authors: YF
authors: Xia
authors: Zheng-tao
authors: ZT
authors: Wang
authors: Qing-long
authors: QL
authors: Guo
authors: Gui-xin
authors: GX
authors: Chou
authors: Yue
authors: Y
authors: Dai
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology; D001175:Arthrography; D015232:Dinoprostone / Q000096:biosynthesis* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood; D007596:Joints / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000097:blood; D053245:RANK Ligand / Q000096:biosynthesis* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000470:Alkaloids; D018501:Antirheumatic Agents; D015850:Interleukin-6; D053245:RANK Ligand; C464745:norisoboldine; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D015232:Dinoprostone
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