TY - JOUR T1 - Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 748 LP - 755 DO - 10.1136/annrheumdis-2016-209757 VL - 76 IS - 4 AU - Augustin Latourte AU - Chahrazad Cherifi AU - Jérémy Maillet AU - Hang-Korng Ea AU - Wafa Bouaziz AU - Thomas Funck-Brentano AU - Martine Cohen-Solal AU - Eric Hay AU - Pascal Richette Y1 - 2017/04/01 UR - http://ard.bmj.com/content/76/4/748.abstract N2 - 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.Conclusion 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. ER -