Integrated Signaling Networks in Osteoarthritis and Aging: From Molecular Mechanisms to Therapeutic Targets

Abstract

Background: Osteoarthritis (OA) is a multifaceted age-related joint disorder resulting from the interplay of metabolic, inflammatory, and senescent pathways. This review combines the most recent research on the interconnected signaling networks in OA and aging. Methods: A systematic search of major databases was performed from 2010 to 2025 in accordance with PRISMA guidelines. Included were studies that examined specific molecular targets and signaling pathways in OA or joint degeneration associated with aging. The Newcastle-Ottawa Scale was used to rate quality. Results: The study shows that OA is a multi-pathway aging disorder that leads to cartilage destruction by combining the senescence-associated secretory phenotype (SASP), epigenetic dysregulation, metabolic dysfunction, and impaired mechanotransduction. The RUNX2/SPP1 axis encourages hypertrophic change, while METTL3-mediated m6A changes stop autophagy. Sirtuins (SIRT1/SIRT6) are essential for regulating metabolism, and Klotho contributes to both Wnt suppression and oxidative stress resistance. Inflammaging is linked to senescence through STAT3, a key mediator of the process. Conclusion: OA is a systemic aging disorder that necessitates multi-target strategies. Senolytic agents, METTL3 inhibitors, SIRT activators, Klotho-based biologics, and combinations targeting STAT3-MAPK-driven inflammaging are among the most important therapeutic directions. For future translation, we need validated biomarkers to group patients and long-term safety data.