We hypothesize that senescent osteoclasts accumulating in subchondral bone of rheumatoid arthritis (RA) joints secrete IL-6 that activates trans-signaling through soluble IL-6R in adjacent synovial fibroblasts, leading to STAT3-mediated suppression of DNMT3a expression. This epigenetic remodeling accelerates the Horvath epigenetic clock specifically in synovial tissue, creating a feed-forward loop: hypomethylated fibroblasts upregulate p16^INK4a and adopt a senescence-associated secretory phenotype (SASP), further recruiting and senescing osteoclasts.

Testable prediction: RA synovial fibroblasts will show 8-15 years of epigenetic age acceleration (measured by Horvath clock CpG sites) compared to osteoarthritis controls, and this acceleration will correlate with subchondral senescent osteoclast density (SA-β-gal+/TRAP+ cells). Selective clearance of senescent osteoclasts with dasatinib (a senolytic with known osteoclast activity) should partially reverse synovial epigenetic age acceleration in a collagen-induced arthritis mouse model within 4 weeks, measurable by bisulfite sequencing of Horvath-ortholog CpG loci in murine synovium.