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

Area of Science:

• Hepatology
• Orthopedics
• Metabolic Diseases

Background:

• Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are linked to bone and joint diseases like osteoporosis and osteoarthritis (OA).
• Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses conditions from simple steatosis to steatohepatitis (MASH), potentially with fibrosis.
• These conditions share increasing prevalence with age.

Purpose of the Study:

• To investigate the contribution of liver injury in metabolic syndrome to skeletal deterioration.
• To establish a mechanistic link between metabolic dysfunction-associated steatohepatitis (MASH) and bone/joint pathology.

Main Methods:

• Male mice were fed a high-fat, cholesterol, and fructose (HFCF) diet to induce MASH and fibrosis.
• Control mice received a nutrient-matched low-fat, cholesterol, and fructose (LFCF) diet.
• Skeletal integrity was assessed using micro-CT of the femur and knee joint analysis.
• Gene expression in knee tissue was analyzed via bulk RNA-sequencing.

Main Results:

• Mice with MASH and fibrosis showed significant cortical thinning, reduced trabecular thickness, and lower bone mineral density in the femur.
• Knee joints exhibited subchondral bone loss, medial cartilage erosion, and increased chondrocyte expression of iNOS, NLRP3, and β-galactosidase.
• Bulk RNA-seq identified upregulated interferon-related and stress-response pathways and downregulated extracellular matrix organization pathways in knee tissue.

Conclusions:

• A mechanistic connection exists between the severity of liver injury in MASH and the deterioration of bone and joint integrity.
• These findings suggest a shared pathophysiological axis between MASLD and osteoarthritis.
• This highlights the potential for therapeutics targeting inflammation or hepatic lipid metabolism to treat both conditions concurrently.