Breaking Down Bones: Hepato-skeletal crosstalk in MASLD-associated fracture susceptibility - PROJECT SUMMARY/ABSTRACT Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD, previously Non-Alcoholic Fatty Liver Disease or NAFLD) affects 30% of people globally. Among these, 1 in 4 have a more severe form of the disease, Metabolic dysfunction-Associated Steatohepatitis (MASH). MASLD and MASH strongly associate with high caloric intake and are highly comorbid with obesity, metabolic syndrome, and type II diabetes. The onset of MASLD is insidious, incurable and it affects a massive proportion of the global population. Persons with MASLD are at increased risk of osteoporosis and fracture. Given the high prevalence of MASLD and massive osteoporosis-related healthcare spending, MASLD-associated skeletal fragility exerts substantial socioeconomic impact. The mechanisms by which skeletal fragility arises in MASLD and MASH are not understood, owing largely to the lack of an appropriate preclinical model. Most mice do not develop MASLD from conditions mimicking the human disease. Uniquely, the Diet Induced Animal Model of NAFLD (DIAMOND) mouse, will develop MASLD and MASH on a high-fat Western diet alone, like humans. The DIAMOND mouse mimics the human phenotype of MASLD and MASH exceptionally well. Using these mice, we demonstrated significant deleterious changes in mechanical strength and geometries of bones from DIAMOND mice fed a high-fat Western diet. In this study, we aim to elaborate histologic bone changes and liver-bone crosstalk driving skeletal fragility in MASLD and MASH. Further, we will describe the role of estrogen in the development of MASLD-associated skeletal fragility, and its role in the sexual dimorphism of the liver and bone phenotype of DIAMOND mice. Finally, we will investigate the skeletal effects of GLP-1 analogs, extremely popular drugs in MASLD management, in mice with MASLD. In Aim 1, we will conduct a longitudinal assessment of the progression of skeletal fragility in DIAMOND mice with MASLD. We will assess bone morphology, biomarkers of bone metabolism, and liver bone crosstalk. These analyses will be correlated with the progression of MASLD on liver histology. In Aim 2, we will leverage the clinical observation that women are relatively protected from skeletal sequelae of MASLD to elaborate a protective role of estrogen. We will ovariectomize female DIAMOND mice to assess the effect of estrogen withdrawal on MASLD-associated skeletal fragility. We will use the same liver and bone phenotype, serum biomarker, and pathway analyses described in Aim 1 to assess the role of estrogen withdrawal in the progression of MASLD bone disease. In Aim 3, we will determine the extent to which GLP-1 analogs rescue bone loss in MASLD via similar outcomes to Aims 1 and 2. While many observational analyses have recently been conducted on bone disease in MASLD, this proposal will be the first prospective study to assess its molecular mechanisms. We aim to discover candidate pathways for novel, effective therapies for this disease.
