Liver injury severity determines skeletal deterioration: a shared pathophysiological axis between MASLD and...

Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) have been linked to osteoporosis and osteoarthritis (OA), where the prevalence of all increase with age. Many individuals with NAFLD also exhibit MetS, a condition that is now termed metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD spans from simple hepatic steatosis to hepatocyte ballooning and inflammation, termed metabolic dysfunction-associated steatohepatitis (MASH), which may occur with or without fibrosis. To delineate the contribution of liver injury to skeletal deterioration within the context of metabolic syndrome (MetS), we fed male mice a high-fat, cholesterol, and fructose (HFCF) diet that induces metabolic syndrome-associated steatohepatitis (MASH) and liver fibrosis, associated with moderate obesity but without profound insulin resistance. A nutrient-matched diet with high carbohydrates but low in fat, cholesterol, and fructose (LFCF), which induced steatosis in adult mice, served as the control. Micro-CT analysis of the femur of HFCF-fed mice that developed MASH with fibrosis revealed significant cortical thinning (reduced bone area and thickness), decreased trabecular thickness, and lower bone mineral density compared to LFCF-fed mice, with no liver fibrosis. In the knee joint, MASH with fibrosis was associated with subchondral bone loss, medial cartilage erosion, and elevated chondrocyte expression of iNOS, NLRP3, and β-galactosidase. Bulk RNA-seq of knee tissue identified 152 differentially expressed genes: interferon-related (Oas3, Nlrc5, Zbp1) and stress-response (Slc6a4, Alox12, Cirbp, Trpc6, Tap1, Ubash3, Nrg1) pathways were upregulated, while extracellular matrix organization pathways were downregulated. Our findings reveal a mechanistic connection between the degree of liver injury and deterioration of bone and joint integrity, pointing to a shared pathophysiological axis in MASLD and OA. Clinically, this raises the prospect that a single therapeutic, designed to modulate inflammation, or hepatic lipid metabolism, could be repurposed or developed to concurrently treat both steatohepatitis and osteoarthritic degeneration.