Journal
MOLECULAR IMMUNOLOGY
Volume 140, Issue -, Pages 70-76Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2021.09.009
Keywords
Trelagliptin; Chondrocyte; Aggrecan; IL-1 beta; SOX-9; AMPK alpha
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Funding
- National Natural Science Foundation of China [81902206]
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Chondrocyte dysregulation is crucial in the development of osteoarthritis, with IL-1 beta playing a key role in activating chondrocytes and degrading ECM. Trelagliptin, a DPP-4 inhibitor used for T2DM, has anti-inflammatory effects and can mitigate IL-1 beta-induced inflammation and oxidative stress in chondrocytes. Trelagliptin protects chondrocyte function and may have a potential role in antagonizing chondrocyte-derived inflammation in OA.
Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of antiinflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1 beta-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) in human chondrocytes. Trelagliptin ameliorates IL-1 beta-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1 beta-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1 beta-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9-reduction by IL-1 beta. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA.
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