Activation of Nrf2/HO-1 signal with Myricetin for attenuating ECM degradation in human chondrocytes and ameliorating the murine osteoarthritis

• Published in: International immunopharmacology 2019-10, Vol.75, p.105742-105742, Article 105742
• Main Authors: Pan, Xiangxiang, Chen, Tingting, Zhang, Zengjie, Chen, Xiaowei, Chen, Chengshu, Chen, Long, Wang, Xiangyang, Ying, Xiaozhou
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Aggrecan; AKT protein; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arthritis; Biomedical materials; Cartilage; Cartilage diseases; Chondrocytes; Chondrocytes - drug effects; Chondrocytes - immunology; Collagen (type II); Collagenase 3; Cyclooxygenase-2; Cytokines; Degradation; Destabilization; Diabetes mellitus; Disease Models, Animal; Enzyme-linked immunosorbent assay; Extracellular Matrix - drug effects; Flavonoids - pharmacology; Flavonoids - therapeutic use; Gene expression; Heme Oxygenase-1 - immunology; Humans; Immunofluorescence; In vivo methods and tests; Inflammation; Interleukin 6; Male; Membrane Proteins - immunology; Meniscus; Mice, Inbred C57BL; Myricetin; NF-E2-Related Factor 2 - immunology; NF-kappa B - immunology; NF-κB; NF-κB protein; Nitric oxide; Nitric-oxide synthase; Nrf2; Osteoarthritis; Osteoarthritis - drug therapy; Osteoarthritis - immunology; Phosphatidylinositol 3-Kinases - immunology; Prostaglandin E2; Proto-Oncogene Proteins c-akt - immunology; Signal transduction; Signaling; Thrombospondin; Western blotting
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.105742

Osteoarthritis (OA), one of the prevailing joint degenerative disorders, contributes to the disability around the world. However, no effective therapeutic was introduced currently. Myricetin was reported to possess the function of anti-inflammatory, anti-diabetic and anti-cancer. Thus, we investigate the protection role of myricetin in OA progression and the potential molecular mechanism in present study. Quantitative realtime PCR and western blotting were performed to evaluate the expression of MMP-13, Aggrecan, iNOS, and COX-2 at both gene and protein levels. An enzyme-linked immunosorbent assay was used to evaluate the levels of inflammatory factors (PGE2, TNF-α, and IL-6). The PI3K/AKT, Nrf2/HO-1 and nuclear factor kappa B (NF-κB) signaling pathways were analyzed by western blotting, and immunofluorescence was used to assess the expression of Nrf2, Collagen II and MMP13. The in vitro effect of myricetin was evaluated by intragastric administration into a mouse osteoarthritis model induced by destabilization of the medial meniscus. Myricetin not only inhibited the generation of inflammatory mediators and cytokines such as nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α and IL-6, but also suppressed the production of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in human chondrocytes under IL-1β stimulation. Moreover, Metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5), which resulted in the degradation of cartilage, were also suppressed in chondrocytes with the treatment of myricetin. To explore the potential mechanism, we found out that myricetin suppressed NF-κB signaling pathway through Nrf2/HO-1 axis in human chondrocytes. Besides, myricetin regulated the Nrf2 signaling pathway through PI3K/Akt pathway. In addition, in vivo study demonstrated that myricetin could ameliorated the progression of OA in mice DMM model through PI3K/Akt mediated Nrf2 signaling pathway. Taken together, our data first demonstrated that myricetin possesses the therapeutic potential on OA through PI3K/Akt mediated Nrf2/HO-1 signaling pathway. •Myricetin attenuates IL-1β induced ECM degradation in chondrocytes.•Myricetin regulates the NF-κB pathway via activation of Nrf2/HO-1 signaling pathway in IL-1β stimulated human chondrocytes.•Myricetin ameliorates the progression of OA in mice DMM model through PI3K/Akt mediated Nrf2 signaling pathway.•Myricetin ameliorates the osteoarthritis in vivo and become a new potential therapeutic for osteo