SIRT1 Downregulation by Advanced Glycation End Products Activates RANKL-Dependent Osteoclast Signaling and Drives...

Advanced glycation end products (AGEs) accumulate with aging and metabolic stress and are increasingly implicated in osteoarthritis (OA) pathology. However, how AGEs regulate osteoclast-chondrocyte signaling remains poorly defined. Here, we integrated proteomic and transcriptomic analyses with machine learning to identify molecular networks altered by AGEs in osteoclasts. SIRT1 emerged as a central regulator suppressed following AGE exposure. Loss of SIRT1 deacetylase activity activated the RANKL/RANK signaling pathway and enhanced osteoclast differentiation. Pharmacological inhibition of RAGE or shRNA-mediated gene silencing restored SIRT1 expression, confirming the upstream role of AGE-RAGE signaling. In a co-culture system, AGE-treated osteoclasts accelerated chondrocyte senescence, as evidenced by elevated senescence markers and SASP factors. Findings were validated in vivo, where AGEs aggravated cartilage degeneration, subchondral bone alterations, and chondrocyte senescence in an OA mouse model. Collectively, these results identify an AGE-driven SIRT1/RANKL axis that links osteoclast activation with chondrocyte aging, highlighting a critical pathway contributing to joint deterioration. Targeting this mechanism may offer new therapeutic opportunities for delaying age-related OA progression.