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Gelsevirine improves age-related and surgically induced osteoarthritis in mice by reducing STING availability and
Meixia Feng1, Depei Kong2, Huan Guo1
1Institute of Translational Medicine, Shanghai University, Shanghai, China.
Abstract:
Low-grade and chronic inflammation is recognized as an important mediator of the pathogenesis of osteoarthritis (OA). The aim of current work was to test the therapeutic effects of gelsevirine on age-related and surgically induced OA in mice and elucidate the underlying mechanism. The in vitro studies revealed that gelsevirine treatment mitigated IL-1β-induced inflammatory response and degeneration in cultured chondrocytes, evidenced by reduced apoptosis and expression of MMP3, MMP9, MMP13, IFNβ, TNFɑ, and Il6, and increased expression of Col2A and Il10. Furthermore, gelsevirine treatment in IL-1β-stimulated chondrocytes reduced the protein expression of stimulator of IFN genes (STING, also referred to Tmem173) and p-TBK1. Importantly, gelsevirine treatment did not provide further protection in STING-deficient chondrocytes against IL-1β stimulation. The in vivo studies revealed that gelsevirine treatment mitigated articular cartilage destruction in age-related and destabilization of the medial meniscus (DMM)-induced OA. Similarly, gelsevirine treatment did not provide further beneficial effects against OA in STING deficient mice. Mechanistically, gelsevirine promoted STING K48-linked poly-ubiquitination and MG-132 (a proteasome inhibitor) reversed the inhibitive effects of gelsevirine on IL-1β-induced activation of STING/TBK1 pathway in chondrocytes. Collectively, we identify that gelsevirine targets STING for K48 ubiquitination and degradation and improves age-related and surgically induced OA in mice.
Insights
Gelsevirine treats osteoarthritis (OA) by targeting the STING pathway. This compound reduces inflammation and cartilage damage in mouse models of OA, offering a potential new therapy.
Area of Science:
- Biomedical Science
- Molecular Biology
- Immunology
Background:
- Osteoarthritis (OA) pathogenesis involves chronic inflammation.
- Identifying novel therapeutic targets for OA is crucial.
Purpose of the Study:
- To evaluate gelsevirine's therapeutic potential in mouse models of osteoarthritis.
- To elucidate the mechanism of gelsevirine's action, focusing on the STING pathway.
Main Methods:
- In vitro studies using cultured chondrocytes stimulated with IL-1β.
- In vivo studies utilizing age-related and surgically induced (DMM) osteoarthritis mouse models.
- Assessment of STING (stimulator of IFN genes) K48-linked poly-ubiquitination and proteasomal degradation.
Main Results:
- Gelsevirine reduced IL-1β-induced inflammation and chondrocyte degeneration in vitro.
- Gelsevirine treatment decreased STING and p-TBK1 protein levels, with no effect in STING-deficient cells.
- Gelsevirine mitigated cartilage destruction in vivo, with diminished efficacy in STING-deficient mice.
- Gelsevirine promoted STING K48 ubiquitination, leading to its degradation via the proteasome.
Conclusions:
- Gelsevirine targets STING for degradation, thereby ameliorating inflammation and cartilage damage in osteoarthritis.
- Gelsevirine demonstrates therapeutic potential for osteoarthritis by modulating the STING signaling pathway.
