Sexual dimorphism of MASLD-driven bone loss.

Area of Science:

• Hepatology and Bone Biology
• Metabolic Syndrome Research
• Preclinical Disease Modeling

Background:

• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent condition with significant risks of progressing to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Hepatocellular Carcinoma (HCC).
• Osteoporosis and bone fractures are increasingly recognized as sexually-dimorphic comorbidities of MASLD, but the underlying mechanisms remain poorly understood.
• The DIAMOND mouse model provides a platform to investigate MASLD progression and associated pathologies, including skeletal complications.

Purpose of the Study:

• To investigate the skeletal phenotype of male and female DIAMOND mice exposed to a Western diet, mimicking MASLD development.
• To identify potential molecular mechanisms, particularly liver-secreted factors, contributing to MASLD-associated bone loss.
• To establish the first preclinical model for studying bone loss in the context of MASLD.

Main Methods:

• DIAMOND mice were fed a Western or control diet for up to 48 weeks, with regular assessment of their skeletal structure and mechanical integrity.
• Analysis of hepatic mRNA expression in DIAMOND mice using the NicheNet database.
• Utilized a parathyroid hormone (PTH)-induced bone loss model to investigate the function of identified candidate ligands.

Main Results:

• Male DIAMOND mice exhibited significant trabecular bone loss by 16 weeks and cortical bone loss with impaired mechanical integrity by 48 weeks.
• Female DIAMOND mice demonstrated protection against MASLD-associated bone loss and skeletal fragility at all assessed timepoints.
• Candidate liver-secreted ligands including CTGF, RARESS2, ANXA2, FGF21, and MMP13 were identified as potential inducers of bone resorption.

Conclusions:

• MASLD induces progressive bone loss and skeletal fragility in male mice, with a notable sex-dimorphic protective effect in females.
• The study implicates specific liver-secreted proteins (CTGF, RARESS2, ANXA2, FGF21, MMP13) as potential mediators of MASLD-driven bone resorption.
• This research provides a foundational preclinical model and identifies novel molecular targets for addressing bone complications in MASLD.