regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-jun n-terminal kinase pathway上游激酶调节炎性关节炎的促分裂原活化蛋白激酶激酶7 c-jun n端激酶途径.pdfVIP

Lee et al. Arthritis Research Therapy 2012, 14:R38 /content/14/1/R38 RESEARCH ARTICLE Open Access Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-Terminal kinase pathway 1,2 1 3 1* Sang-il Lee , David L Boyle , Andres Berdeja and Gary S Firestein Abstract Introduction: The c-Jun N-terminal kinase (JNK) is a key regulator of matrix metalloproteinase (MMP) and cytokine production in rheumatoid arthritis (RA) and JNK deficiency markedly protects mice in animal models of arthritis. Cytokine-induced JNK activation is strictly dependent on the mitogen-activated protein kinase kinase 7 (MKK7) in fibroblast-like synoviocytes (FLS). Therefore, we evaluated whether targeting MKK7 using anti-sense oligonucleotides (ASO) would decrease JNK activation and severity in K/BxN serum transfer arthritis. Methods: Three 2’-O-methoxyethyl chimeric ASOs for MKK7 and control ASO were injected intravenously in normal C57BL/6 mice. PBS, control ASO or MKK7 ASO was injected from Day -8 to Day 10 in the passive K/BxN model. Ankle histology was evaluated using a semi-quantitative scoring system. Expression of MKK7 and JNK pathways was evaluated by quantitative PCR and Western blot analysis. Results: MKK7 ASO decreased MKK7 mRNA and protein levels in ankles by about 40% in normal mice within three days. There was no effect of control ASO on MKK7 expression and MKK7 ASO did not affect MKK3, MKK4 or MKK6. Mice injected with MKK7 ASO had significantly less severe arthritis compared with control ASO (P 0.01). Histologic evidence of synovial inflammation, bone erosion and cartilage damage was reduced in MKK7 ASO- treated mice (P 0.01). MKK7 deficiency decreased phospho-JNK and phospho-c-Jun