Senescent Osteoclast-Derived EVs Drive Inflammaging-Mediated Erosive Arthritis via Epigenetic Reprogramming of Synovial Macrophages

Hypothesis: Senescent osteoclasts accumulating in subchondral bone with aging release extracellular vesicles (EVs) enriched in miR-34a and hypomethylated mitochondrial DNA fragments. These EVs are taken up by synovial tissue-resident macrophages, where they inhibit SIRT1-dependent deacetylation of NF-kB p65 and activate cGAS-STING signaling, epigenetically reprogramming macrophages toward a sustained pro-inflammatory (SASP-like) secretome.

This creates a feed-forward loop: senescent osteoclast EVs → macrophage inflammaging → accelerated osteoclastogenesis → more senescent osteoclasts.

Testable prediction: Selective clearance of p16^INK4a-positive osteoclasts using bone-targeted senolytics (dasatinib conjugated to bisphosphonate scaffolds) would reduce synovial macrophage SASP markers (IL-6, MMP-3, CXCL10) by >40% in aged mice with collagen-induced arthritis at 8 weeks post-treatment.

Experimental design: Use p16-3MR transgenic mice with GCV-mediated senescent cell ablation restricted to the osteoclast lineage (LysM-Cre x p16-3MR). Compare synovial fluid cytokine profiles and H3K27ac ChIP-seq on macrophage inflammatory gene promoters between ablated and control groups.

A positive result would establish senescent osteoclasts as an upstream driver of age-related erosive arthritis and validate bone-targeted senolysis as a disease-modifying strategy at the intersection of geroscience and rheumatology.