title: Inhibition of inflammatory bone erosion by constitutively active STAT-6 through blockade of JNK and NF-kappaB activation.
abstract: OBJECTIVE
  NF-kappaB and JNK signaling pathways play key roles in the pathogenesis of inflammatory arthritis. Both factors are also activated in response to osteoclastogenic factors, such as RANKL and tumor necrosis factor alpha. Inflammatory arthritis and bone erosion subside in the presence of antiinflammatory cytokines such as interleukin-4 (IL-4). We have previously shown that IL-4 inhibits osteoclastogenesis in vitro through inhibition of NF-kappaB and JNK activation in a STAT-6-dependent manner. This study was undertaken to investigate the potential of constitutively active STAT-6 to arrest the activation of NF-kappaB and JNK and to subsequently ameliorate the bone erosion associated with inflammatory arthritis in mice.
  
  
  METHODS
  Inflammatory arthritis was induced in wild-type and STAT-6-null mice by intraperitoneal injection of arthritis-eliciting serum derived from K/BxN mice. Bone erosion was assessed in the joints by histologic and immunostaining techniques. Cell-permeable Tat-STAT-6 fusion proteins were administered intraperitoneally. Cells were isolated from bone marrow and from joints for the JNK assay, the DNA-binding assays (electrophoretic mobility shift assays), and for in vitro osteoclastogenesis.
  
  
  RESULTS
  Activation of NF-kappaB and JNK in vivo was increased in extracts of cells retrieved from the joints of arthritic mice. Cell-permeable, constitutively active STAT-6 (i.e., STAT-6-VT) was effective in blocking NF-kappaB and JNK activation in RANKL-treated osteoclast progenitors. More importantly, STAT-6-VT protein significantly inhibited the in vivo activation of NF-kappaB and JNK, attenuated osteoclast recruitment in the inflamed joints, and decreased bone destruction.
  
  
  CONCLUSIONS
  Our findings indicate that the administration of STAT-6-VT presents a novel approach to the alleviation of bone erosion in inflammatory arthritis.
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Hirayama
authors.forename: Simon
authors.initials: S
authors.lastname: Dai
authors.forename: Sabiha
authors.initials: S
authors.lastname: Abbas
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007867:Leg Bones / Q000187:drug effects* / Q000473:pathology; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D002352:Carrier Proteins; D004338:Drug Combinations; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D015534:Trans-Activators; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases