ARID1A Mediates ROS-Induced Osteoclast Activation in TMJ Osteoarthritis.

Abstract

Excessive osteoclast activation drives rapid subchondral bone destruction, serving as a critical early-stage event precipitating temporomandibular joint osteoarthritis (TMJ-OA). Although epigenetic remodeling is widely recognized as an important interface between pathological environmental signals and genomic response, the specific epigenetic mechanisms translating TMJ-OA-associated stimulation into pathological osteoclast activation remain to be elucidated. Here, using a mechanically induced TMJ-OA mouse model, we identify aberrant reactive oxygen species (ROS) accumulation as a critical upstream driver initiating excessive osteoclast activation and subsequent joint deterioration. By integrating transcriptomic and epigenomic analyses, we delineate the chromatin remodeler AT-rich interaction domain 1A (ARID1A) as an essential oxidative stress sensor within the osteoclast lineage. Mechanistically, ROS accumulation induces ARID1A upregulation and recruitment to the Src enhancer, transcriptionally activating Src and amplifying PI3K-AKT signaling to drive pathological osteoclastogenesis. Conditional knockout of Arid1a in myeloid cells effectively abrogates subchondral bone loss and cartilage destruction in TMJ-OA. Translating these mechanistic insights, we engineered an ROS-responsive, osteoclast-targeting hydrogel for the on-demand delivery of an ARID1A-dependent canonical BRG1/BRM-associated factor complex inhibitor, which successfully alleviates TMJ-OA progression. Our findings establish the epigenetic response to ROS accumulation as a key pathogenic mechanism in TMJ-OA and highlight ARID1A as a promising therapeutic target for early disease intervention.