MDL‐800‐induced SIRT6 activation decreases age‐associated osteoarthritis in mice

Objective SIRT6 is a nuclear‐localized histone deacetylase that regulates multiple pathways associated with aging. This study aimed to determine whether systemic administration of a small molecule activator of SIRT6, MDL‐800, decreases the severity of age‐associated osteoarthritis (OA) in mice. Methods Male 18‐month‐old mice received weekly intraperitoneal injections of MDL‐800 or vehicle control for 6 months, and OA severity was assessed at 24 months using histology, micro‐CT, and histomorphometry. The role of MDL‐800‐induced SIRT6 activation in human chondrocyte function was analyzed using RNA sequencing and immunoblotting. The effect of MDL‐800 to reduce DNA damage was assessed in human and mouse synovial fibroblasts by the comet assay. Results Mice receiving long‐term administration of MDL‐800 were protected from OA pathology when compared to controls, as characterized by less cartilage damage, osteophyte formation, synovial hyperplasia, subchondral bone sclerosis, and meniscal ossification. RNA sequencing of chondrocytes revealed that MDL‐800 negatively enriched pathways associated with bone formation, angiogenesis, and catabolic MAP kinase signaling, while positively enriching pathways associated with epigenetic regulation, telomere maintenance, mitochondrial function, redox balance, and DNA repair. MDL‐800 significantly decreased oxidative stress‐induced phosphorylation of p38 in chondrocytes and basal DNA damage in human and mouse synovial fibroblasts. Conclusions Activation of SIRT6 by MDL‐800 significantly protected old mice from age‐associated OA severity in vivo . MDL‐800 decreased pathways associated with pathological bone formation and regulated multiple hallmarks of aging. Targeted therapies that activate SIRT6 may represent a novel strategy to repress multiple aging pathways to slow, stop, or reverse age‐associated OA.