is presented as a central mechanism and therapeutic target in osteoarthritis progression.
Evidence
This review summarizes mechanistic evidence on inflammation, mechanical stress, metabolic and signaling dysregulation, genetics-related alterations, and senescence-targeted OA interventions under preclinical or clinical investigation.
Caveat
The therapeutic case remains limited by unresolved questions about specificity, safety, and long-term efficacy.
Simplified
PurposeThis review aims to elucidate the mechanisms underlying in osteoarthritis (OA) from 4 core perspectives: extracellular inflammation, mechanical overload and stress, intracellular metabolic and signaling dysregulation, and genetics-related alterations. It further summarizes emerging therapeutic strategies targeting chondrocyte senescence to address the unmet clinical need for disease-modifying OA interventions.FindingsAccumulating evidence indicates that chondrocyte senescence drives OA progression through multiple interconnected mechanisms. These include amplification of inflammation and extracellular matrix degradation via the senescence-associated secretory phenotype (), disruption of anabolic-catabolic homeostasis, dysregulation of mechanotransduction pathways under excessive mechanical load, and reshaping of intracellular metabolism and redox balance. Additional contributing mechanisms involve epigenetic dysregulation, non-coding RNA-mediated gene modulation, and impaired autophagy. Therapeutic approaches under preclinical or clinical investigation encompass senolytic and senomorphic agents, chondroprotective biological materials, genetic or RNA-based interventions, as well as strategies targeting SASP modulation and extracellular microenvironment repair.ConclusionsChondrocyte senescence serves as a central convergent mechanism in OA pathogenesis and a promising target for disease-modifying therapies. Advances in mechanistic understanding and senescence-targeted interventions offer new avenues for translational innovation, though critical challenges related to specificity, safety, and long-term efficacy require further resolution.
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