METTL5 deficiency impairs osteogenesis through OSER1-dependent antioxidant regulation

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Methyltransferase-like 5 (METTL5) is crucial for rRNA m6A modification.
• METTL5 mutations link to skeletal and cognitive disorders.
• Molecular mechanisms of METTL5-related disorders are unclear.

Purpose of the Study:

• Investigate METTL5's role in skeletal development.
• Elucidate the molecular mechanisms of METTL5 deficiency.
• Evaluate N-acetylcysteine (NAC) as a therapeutic intervention.

Main Methods:

• Generated Mettl5 knockout (KO) mice.
• Assessed bone mass, body size, and osteogenic differentiation.
• Analyzed mRNA translation efficiency and antioxidant gene expression.
• Administered NAC to Mettl5-KO mice.

Main Results:

• Mettl5 KO mice exhibited reduced bone mass and body size.
• Mettl5 deficiency impaired mesenchymal stem cell osteogenic differentiation.
• METTL5 deficiency decreased translation of oxidative stress-responsive mRNA and antioxidant capacity.
• NAC administration partially rescued skeletal defects in Mettl5-KO mice.

Conclusions:

• METTL5 plays a vital role in maintaining antioxidant defense.
• Mettl5 deficiency impacts skeletal development via oxidative stress pathways.
• NAC supplementation shows therapeutic potential for METTL5-related disorders.