Cellular senescence — where chondrocytes enter irreversible cell-cycle arrest while resisting apoptosis, ferroptosis, and pyroptosis — drives knee osteoarthritis (OA) progression through the senescence-associated secretory phenotype (SASP). SASP releases pro-inflammatory cytokines and signaling molecules that degrade cartilage and, critically, induce senescence in neighboring cells via autocrine signaling, creating a self-amplifying destructive loop. Both senolytics (drugs that clear senescent cells) and senomorphics (agents that neutralize SASP without killing senescent cells) have demonstrated improved OA pathogenesis in preclinical in vitro and in vivo models, and multiple clinical trials in knee OA have now been initiated.
This review arrives at a pivotal moment: the senotherapy field has rapidly matured from animal models toward human trials, with compounds like dasatinib plus quercetin and navitoclax among the leading senolytic candidates tested systemically. What distinguishes OA as an attractive target is the localized, intra-articular delivery route, which could minimize the systemic toxicity concerns that plague broad senolytic use. However, the abstract flags a critical unresolved problem — safety profiling and dosing optimization remain incomplete. Chondrocytes are post-mitotic and largely non-renewable, meaning overly aggressive senescent cell clearance risks collateral cartilage damage. The field also lacks validated biomarkers to quantify chondrocyte senescence burden in living joints. Overall, this represents genuinely promising but early-stage translational science — confirmatory rather than paradigm-shifting for now, with the real test hinging on ongoing clinical trial outcomes.
