Sexual dimorphism of MASLD-driven bone loss.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is highly prevalent with major risk of progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Hepatocellular Carcinoma (HCC). Recently, osteoporosis and bone fracture have emerged as sexually-dimorphic comorbidities of MASLD yet the mechanisms of this bone loss are unknown. Herein, we address these knowledge gaps using DIAMOND mice which develop MASLD, MASH, and HCC via Western diet exposure. We examined the skeletal phenotype of male DIAMOND mice after 16, 36, and 48 weeks of exposure to Western or control diet. At 16 weeks, male DIAMOND mice with MASLD lose trabecular bone but retain mechanical bone integrity. At 48 weeks, males lose cortical bone and mechanical integrity, indicating severe skeletal weakening. Female DIAMOND mice were protected from cortical and trabecular MASLD-associated bone loss and skeletal fragility at all timepoints. Using NicheNet, a publicly available database of hepatic mRNA expression in DIAMOND mice, and a PTH-induced model of bone loss, we suggest Ctgf, Rarres2, Anxa2, Fgf21, and Mmp13 are liver-secreted ligands inducing bone resorption. This study is the first preclinical investigation of bone loss in MASLD, and the first to suggest the role of Ctgf, Rarrest2, Anxa2, Fgf21, and Mmp13 as drivers of this pathology.