CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy.

Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease with few treatment options. The pathogenesis of OA is characterized by sustained inflammation, oxidative stress and chondrocyte apoptosis that eventually lead to cartilage degradation and joint dysfunction. In the present study, we identified a synthetic triterpenoid CDDO-Im(1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) as an activator of Nrf2 (nuclear factor erythroid 2-related factor 2) that displayed strong anti-OA effects. We showed that CDDO-Im (20 nM) significantly alleviated TNF-α-induced apoptosis of primary human chondrocytes and extracellular matrix degradation. In a mouse OA model incurred by DMM (destabilization of medial meniscus), administration of CDDO-Im (2.5 mg/kg, ip, every other day for 8 weeks) effectively reduced knee joint cartilage erosion and serum levels of inflammatory cytokines IL-1ß and IL-6. We revealed that CDDO-Im (20 nM) significantly enhanced autophagy activities in chondrocytes, whereas the autophagy inhibition by chloroquine (CQ, 50 µM) or 3-methyladenine (3-MA, 5 mM) abrogated the anti-apoptosis and chondroprotective effects of CDDO-Im in TNF-α-treated chondrocytes. Moreover, we confirmed that CDDO-Im (1-20 nM) dose-dependently activated Nrf2 pathway in TNF-α-treated chondrocytes, and its chondroprotective and autophagy-enhancing effects were significantly diminished when Nrf2 signaling was blocked by Nrf2 inhibitor ML385 (20 µM) or siRNA-mediated Nrf2 knockdown. Together, our results demonstrate that CDDO-Im exhibits prominent chondroprotective and anti-OA activities owing to its Nrf2 activation and autophagy-enhancing properties, which might provide new insights into the strategies of OA clinical prevention and treatment.

A randomized double blind, placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis.

OBJECTIVE: To assess the efficacy of topical Tripterygium wilfordii (TW), a Chinese herbal therapy, in rheumatoid arthritis (RA). METHODS: A 6 week randomized double blind placebo controlled study of 61 patients with RA meeting American College of Rheumatology (ACR) criteria was conducted in China. The primary outcome was a modified ACR-20 response rate, analyzed by logistic regression analysis. RESULTS: The modified ACR-20 response rate differed significantly (topical TW 58% vs placebo 20%; p = 0.002). There was an 8.1-fold (95% CI 1.9-35.4) increase in the modified ACR-20 response for the TW compared to the placebo group, adjusted for age and erythrocyte sedimentation rate. CONCLUSION: Topical TW appears efficacious for the treatment of RA, but larger studies are needed.