A liver-cartilage selenium axis underlies metabolic comorbidity in osteoarthritis

Abstract

While osteoarthritis (OA) has traditionally been viewed as a localized joint disorder, systemic metabolic dysfunction is increasingly recognized as a key contributor to its pathogenesis. Here, we identify a liver-cartilage micronutrient axis in which hepatic dysfunction promotes OA through impaired selenium (Se) metabolism. Nationwide cohorts reveal elevated OA prevalence among individuals with liver disease. In murine models of acute and chronic liver injury and metabolic dysfunction-associated steatohepatitis (MASH), hepatic dysfunction disrupts the selenoprotein P (SELENOP)-ApoER2 axis, compromising Se delivery to cartilage. Mechanistically, hepatic stress reduces hepatocyte SELENOP output through convergent transcriptional repression and translational suppression via ribosome collision on selenocysteine (Sec)-rich SELENOP transcripts. The resulting cartilage selenoprotein deficiency promotes chondrocyte senescence, exacerbating OA. Inorganic Se supplementation bypasses impaired SELENOP-mediated Se delivery, restoring chondrocyte selenoproteins and alleviating OA, highlighting Se as a nutritionally modifiable factor. Our findings suggest preventive strategies against joint comorbidity in the growing population with metabolic liver disease.