Exploiting senescence as a therapeutic target in osteoarthritis

Osteoarthritis (OA) is a complex degenerative joint disease with significant socioeconomic impact worldwide. Senescence, marked by permanent cell cycle arrest and acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP), affects chondrocytes, synovial cells and stem cells alike, disrupting cartilage homeostasis and integrity, ultimately contributing to OA pathogenesis and progression. Therapeutic strategies that target cellular senescence to mitigate OA include senolytics, senomorphics and stem cell rejuvenation approaches. Senolytics, such as navitoclax and dasatinib-quercetin combinations, selectively induce apoptosis in senescent cells, alleviating their detrimental effects on joint tissues. Emerging senolytic approaches involve sirtuin activation, autophagy induction, and leveraging natural compounds like resveratrol, metformin, and vitamin D3 to restore chondrocyte function. Senomorphics, in contrast, aim to modulate the SASP to reduce inflammation and tissue degradation while preserving cartilage integrity. Cell-rejuvenation therapies, such as exosome-based treatments and gene therapy, show promise in rejuvenating senescent mesenchymal stem cells to mitigate OA progression. Despite promising preclinical advancements, challenges remain in translating these therapies into clinical applications due to the complexity of senescence-driven mechanisms and potential side effects. This review explores the detrimental role of senescence in OA and the evolving senescence-targeted therapeutic landscape that holds potential to revolutionize OA management and improve patient outcomes.