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SAT0035 Chondroprotective Effects of IL-6 Inhibition Through Blockade of the STAT3 Pathway
  1. A. Latourte1,
  2. C. Cherifi1,
  3. H.-K. Ea1,2,
  4. W. Bouaziz1,
  5. T. Funck-Brentano1,2,
  6. M. Cohen Solal1,2,
  7. E. Hay1,
  8. P. Richette1,2
  1. 1INSERM U1132, Centre Viggo Petersen and Université Paris Diderot - Paris 7
  2. 2Fédération de Rhumatologie, Centre Viggo Petersen, Hôpital Lariboisière, Paris, France

Abstract

Background High levels of interleukin-6 (IL-6) have been found in the synovial fluid of patients with osteoarthritis (OA), suggesting that IL-6 may be involved in the pathogenesis of OA.

Objectives To investigate the effects of IL-6 in chondrocytes and to determine its main signalling pathways. To study the impact of IL-6 inhibition in an experimental mice model of OA.

Methods The effects of IL-6 (10-50-100 ng/mL) were determined in vitro (primary culture of mouse chondrocytes) and ex vivo (mouse femoral head articular cartilage). Proteoglycan content (Alcian blue and Safranin O staining, DMM blue assay), expression of catabolic factors (qPCR, Western Blot, immunostaining), NO and PGE2 production and apoptosis (TUNEL assay) were evaluated. IL-6-induced signalling pathways were determined by Western Blot. The impact of STAT3 blockade was investigated using a specific inhibitor – Stattic – ex vivo and in a mice model of OA induced by destabilization of the medial meniscus (DMM).

Results In vitro and ex vivo, IL-6 dose-dependently induced a dramatic loss of proteoglycan content through an increase in the expression of MMP3, MMP13, ADAMTS4 and ADAMTS5. By contrast, IL-6 had no effect on col2, aggrecan, col10 or VEGF. IL-6 induced chondrocytes apoptosis without increasing NO or PGE2 production. Inhibition of STAT3 by Stattic counteracted the catabolic and pro-apoptotic effects of IL-6 ex vivo. Finally, we orally administrated either Stattic (25 mg/kg/2d) or a saline for 6 weeks in C57/Bl6 mice (n=18) subjected to DMM. The severity of the OA lesions as assessed with the OARSI histological score was significantly lower in the Stattic group: 2.65±1.44 vs. 4.5±0.93 (p=0,004).

Conclusions Our findings indicate that IL-6 has numerous catabolic effects in cartilage, mainly mediated by STAT3. STAT3 blockade protects against DMM-induced OA in mice, suggesting that IL-6 might be a promising therapeutic target in OA.

Disclosure of Interest None declared

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