title: Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis.
abstract: OBJECTIVE
  To investigate the impact of systemic inhibition of interleukin 6 (IL-6) or signal transducer and activator of transcription (Stat3) in an experimental model of osteoarthritis (OA).
  
  
  METHODS
  Expression of major catabolic and anabolic factors of cartilage was determined in IL-6-treated mouse chondrocytes and cartilage explants. The anti-IL-6-receptor neutralising antibody MR16-1 was used in the destabilisation of the medial meniscus (DMM) mouse model of OA. Stat3 blockade was investigated by the small molecule Stattic ex vivo and in the DMM model.
  
  
  RESULTS
  In chondrocytes and cartilage explants, IL-6 treatment reduced proteoglycan content with increased production of matrix metalloproteinase (MMP-3 and MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS-5). IL-6 induced Stat3 and extracellular signal-regulated kinase (ERK) 1/2 signalling but not p38, c-Jun N-terminal kinase or Akt. In the DMM model, Stat3 was activated in cartilage, but neither in the synovium nor in the subchondral bone. Systemic blockade of IL-6 by MR16-1 alleviated DMM-induced OA cartilage lesions, impaired the osteophyte formation and the extent of synovitis. In the same model, Stattic had similar beneficial effects on cartilage and osteophyte formation. Stattic, but not an ERK1/2 inhibitor, significantly counteracted the catabolic effects of IL-6 on cartilage explants and suppressed the IL-6-induced chondrocytes apoptosis.
  
  
  CONCLUSIONS
  IL-6 induces chondrocyte catabolism mainly via Stat3 signalling, a pathway activated in cartilage from joint subjected to DMM. Systemic blockade of IL-6 or STAT-3 can alleviate DMM-induced OA in mice.
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.|Rheumatology Department, University Paris Diderot, Hôpital Lariboisière, Paris, France.
authors: Augustin
authors: A
authors: Latourte
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.
authors: Chahrazad
authors: C
authors: Cherifi
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.|Rheumatology Department, University Paris Diderot, Hôpital Lariboisière, Paris, France.
authors: Jérémy
authors: J
authors: Maillet
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.|Rheumatology Department, University Paris Diderot, Hôpital Lariboisière, Paris, France.
authors: Hang-Korng
authors: HK
authors: Ea
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.
authors: Wafa
authors: W
authors: Bouaziz
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.|Rheumatology Department, University Paris Diderot, Hôpital Lariboisière, Paris, France.
authors: Thomas
authors: T
authors: Funck-Brentano
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.|Rheumatology Department, University Paris Diderot, Hôpital Lariboisière, Paris, France.
authors: Martine
authors: M
authors: Cohen-Solal
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.
authors: Eric
authors: E
authors: Hay
authors: INSERM U1132, Hôpital Lariboisière, Paris, France.|Rheumatology Department, University Paris Diderot, Hôpital Lariboisière, Paris, France.
authors: Pascal
authors: P
authors: Richette
mesh_terms: D000071121:ADAMTS4 Protein / Q000378:metabolism; D000071116:ADAMTS5 Protein / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002356:Cartilage / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000378:metabolism* / Q000517:prevention & control; D054850:Osteophyte / Q000517:prevention & control; D011509:Proteoglycans / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013585:Synovitis / Q000517:prevention & control; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000906:Antibodies; D003499:Cyclic S-Oxides; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C494087:Stat3 protein, mouse; C517409:stattic
keywords: Chondrocytes; Cytokines; Osteoarthritis