Osteoarthritis (OA) is a multifactorial degenerative disorder entailing cartilage loss and progressive joint failure. m6A RNA methylation could impact multiple disorders, including OA. In this study, m⁶A methylation regulator WTAP was down-regulated in OA cartilage, accompanied by significantly lower m⁶A methylation levels in OA tissues. In the DMM-induced mice OA model and IL-1β- or TNF-α-stimulated chondrocytes, WTAP and m⁶A methylation levels were decreased, but IL-1β, IL-6, and TNF-α cytokine expressions were elevated. In vivo and in vitro, WTAP overexpression increased m⁶A methylation levels but reduced proinflammatory cytokine contents. Furthermore, WTAP overexpression (OE) increased chondrocyte viability and proliferation, aggrecan and collagen II protein, and decreased cell apoptosis, MMP3, MMP13, and ADAMTS5. WTAP-mediated m⁶A methylation of IL-33 and impaired IL-33 mRNA stability. IL-33 OE caused no changes to WTAP expression; however, IL-33 OE partially attenuated WTAP OE-induced IL-33 downregulation. IL-33 overexpression inhibited chondrocyte viability and proliferation, decreased aggrecan and collagen II but elevated MMP3, MMP13, and ADAMTS5, and increased cell apoptosis and proinflammatory cytokine contents. More importantly, IL-33 eliminated the effects of WTAP OE on chondrocytes. Therefore, WTAP is down-regulated in OA; WTAP improves chondrocyte proliferation and function, thereby ameliorating OA through mediating m⁶A methylation of IL-33 and impairing IL-33 mRNA stability.

01 Feb 2025·Cytotechnology

Triptolide attenuates LPS-induced chondrocyte inflammation by inhibiting inflammasome activation via the Wnt/β-catenin and NF-κB signaling pathways

Article

Author: Liu, Qiming ; Zou, Yang ; Shi, Hangchu ; He, Wang ; Ma, Xuming ; Shen, Xiaoqiang

Osteoarthritis (OA) is a common form of arthritis characterized by subchondral bone proliferation and articular cartilage degeneration. Recently, the Nod-like receptor pyrin domain 3 (NLRP3) inflammasome has gained attention due to its association with synovial inflammation in OA. Triptolide (TP), known for its immunosuppressive and anti-inflammatory effects, has been studied in various diseases. However, the specific impact of TP on OA and its underlying mechanism remains largely unexplored. In this study, chondrocytes were treated with a specific concentration of TP, and subsequent analysis through Western blotting and immunofluorescence staining revealed decreased expression levels of MMP-13, NLRP3, Caspase-1, ASC, β-catenin, p-p65, and IκB compared to the model group. ELISA results demonstrated significantly lower levels of IL-1β, IL-18, and TNF-α in the TP treatment group compared to the model group. In addition, triptolide ameliorates the degradation of the extracellular matrix (ECM) by enhancing the expression of collagen-II. In conclusion, our findings suggest that TP exhibits anti-inflammatory effects on chondrocytes in the presence of LPS-induced inflammation by inhibiting the activation of the NLRP3 inflammasome via the Wnt/β-catenin and NF-κB pathway. These results contribute to a better understanding of TP's potential therapeutic benefits in managing OA.

01 Feb 2025·Journal of Cellular and Molecular Medicine

Pioglitazone Regulates Chondrocyte Metabolism and Attenuates Osteoarthritis by Activating Peroxisome Proliferator‐Activated Receptor Gamma

Article

Author: Shi, Jiaqi ; Gong, Tianlun ; Zhou, Yi

ABSTRACTOsteoarthritis presents a significant clinical challenge due to its high prevalence and the resultant impairment of patients' motor function. Osteoarthritic chondrocytes are characterised by inflammation and metabolic disturbances. Pioglitazone, an agonist of peroxisome proliferator‐activated receptor γ (PPAR‐γ), has been demonstrated to exert anti‐inflammatory effects across various diseases. This study aims to investigate the potential protective effects of Pioglitazone on osteoarthritic chondrocytes. An in vitro chondrocyte inflammation model was established utilising IL‐1β. The impact of Pioglitazone on chondrocyte inflammation and extracellular matrix synthesis was evaluated through enzyme‐linked immunosorbent assay, immunofluorescence staining and Alcian blue staining. The affinity of Pioglitazone for PPAR‐γ was investigated using molecular docking techniques. Alterations in chondrocyte glycolysis and oxidative phosphorylation were examined using the Seahorse XF Analyser, and the influence of Pioglitazone on glucose uptake and the mitochondrial electron transport chain was further analysed. Pioglitazone was gavaged in a mouse OA model established by anterior cruciate ligament transection to evaluate the therapeutic efficacy of Pioglitazone. Our findings indicate that Pioglitazone mitigates chondrocyte inflammation and osteoarthritis in murine models by inhibiting the expression of inflammatory mediators such as TNF‐α, IL‐6 and PGE2, and by preventing the degradation of aggrecan and collagen II. Furthermore, Pioglitazone significantly upregulated the expression of glucose transporter 1 and stabilised the mitochondrial proton delivery chain in a PPAR‐γ‐dependent manner, thereby enhancing chondrocyte glucose uptake, glycolysis, and oxidative phosphorylation. These effects were partially reversed by the PPAR‐γ antagonist GW9662. Pioglitazone can confer chondroprotective benefits in osteoarthritis by activating PPAR‐γ.

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