title: Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis.
abstract: OBJECTIVE
  Previous studies have demonstrated that inhibition of c-Jun N-terminal kinase (JNK) decreases joint destruction in the rat adjuvant arthritis model. The present study was undertaken to investigate whether selective loss of JNK-2 function decreases joint destruction in JNK-2 knockout mice, in order to determine the role of this isoform in inflammatory arthritis.
  
  
  METHODS
  Passive collagen-induced arthritis (CIA) was induced in Jnk2(-/-) and wild-type mice by administering anti-type II collagen antibodies. Arthritis was assessed daily using a semiquantitative clinical scoring system. Fibroblast-like synoviocytes (FLS) were prepared from Jnk2(-/-) and wild-type mice, and JNK protein expression was determined by Western blot analysis. Matrix metalloproteinase 13 (MMP-13) expression was determined by Northern blot analysis, and activator protein 1 (AP-1) binding activity by electromobility shift assay (EMSA).
  
  
  RESULTS
  The JNK protein level in Jnk2(-/-) mice with CIA was 22% of that in wild-type mice with CIA (P < 0.001), and mainly the 46-kd isoform was expressed in the former group. Surprisingly, clinical arthritis was slightly more severe in the Jnk2(-/-) mice. Histologic scores for synovial inflammation were not significantly different. However, Safranin O-stained sections from the Jnk2(-/-) mice exhibited significantly less joint damage. Although joint destruction was decreased in Jnk2(-/-) mice with CIA, EMSA and Northern blot analysis of total joint extracts revealed similar levels of AP-1 binding and MMP-13 expression in Jnk2(-/-) and wild-type mice. The lack of correlation with AP-1 activity and MMP expression was probably because non-FLS cells in the joint may express more JNK-1 than do FLS.
  
  
  CONCLUSIONS
  JNK-2 is a determinant of matrix degradation, but it has little effect on inflammation in arthritis. Complete inhibition of MMP expression and joint destruction will likely require combined JNK-1 and JNK-2 inhibition.
authors.affiliation: University of California San Diego School of Medicine, La Jolla 92093, USA.
authors.forename: Zuoning
authors.initials: Z
authors.lastname: Han
authors.forename: Lufen
authors.initials: L
authors.lastname: Chang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamanishi
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology*; D017364:Collagenases / Q000235:genetics; D015870:Gene Expression; D048031:JNK Mitogen-Activated Protein Kinases; D007596:Joints / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D018808:Transcription Factor AP-1; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases