ECTS Abstracts (2015) 1 OC5.1

Inhibition of the interleukin-6-induced STAT3 signalling pathway is chondroprotective

Augustin Latourte1,2, Chahrazad Cherifi1, Hang Korng Ea1,2, Wafa Bouaziz1, Thomas Funck-Brentano1,2, Martine Cohen-Solal1,2, Eric Haÿ1 & Pascal Richette1,2

1INSERM UMR-1132, Hôpital Lariboisière, Paris, France; 2Fédération de Rhumatologie, Centre Viggo Petersen - Hôpital Lariboisière, Paris, France.

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. The objectives were to investigate the effects of IL-6 in chondrocytes and to determine its main signalling pathways; and 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 destabilisation 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 per 2 day) 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).

Conclusion: 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: The authors declared no competing interests. This work was supported by the Société Française de Rhumatologie.

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