Molecular basis of senescence in osteoarthritis

Abstract

Osteoarthritis (OA) is a multifaceted degenerative joint disorder with substantial global socioeconomic implications. Cellular senescence, defined by permanent cell cycle arrest, has been identified as a critical contributor to OA progression, driving the disruption of cartilage homeostasis and structural integrity. Here, we first delve into the molecular triggers of senescence in OA, including impaired DNA damage response, telomere shortening, mitochondrial dysfunction, oxidative and autophagic stresses, epigenetic modifications, and dysregulated sirtuins and noncoding RNAs. These factors collectively contribute to the establishment of a senescent phenotype in joint tissues, perpetuating the degenerative processes observed in OA. Later, we present the pro-inflammatory senescence-associated secretory phenotype (SASP) as a driving force behind senescence-mediated OA progression that fuels chronic inflammation via the release of pro-inflammatory cytokines, chemokines, and matrix-degrading enzymes, disrupts tissue repair mechanisms, and alters the microenvironment to favor catabolic processes, further exacerbating joint degeneration. The interplay between these factors highlights the complexity of senescence-driven degeneration in OA, underscoring the need for deeper insights into molecular basis of the disease. This review aims to illuminate these mechanisms, providing a foundation for understanding the cellular and molecular pathways that drive senescence in OA and identifying knowledge gaps to guide future research on this pervasive disease.