Integrative Analysis and Experimental Validation Identify Potential m6A-Related Biomarkers for Osteoporosis

Area of Science:

• Epigenetics
• Immunology
• Biomarker Discovery

Background:

• Osteoporosis (OP) is a complex skeletal disorder.
• The role of N6-methyladenosine (m6A) regulators and the immune microenvironment in OP pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of m6A regulators in OP.
• To identify potential m6A-related biomarkers for OP risk assessment and treatment.
• To explore the interplay between m6A regulators and the immune microenvironment in OP.

Main Methods:

• Analysis of GEO datasets for differential expression of 22 m6A regulators and immune infiltration.
• Consensus clustering and m6Ascore grouping to define molecular subtypes.
• Machine learning for biomarker identification and nomogram construction.
• Experimental validation using peripheral blood monocytes (PBMCs) transcriptome sequencing and Western blot.

Main Results:

• Identified differential expression of m6A regulators (e.g., FTO, HNRNPC, METTL4, CBLL1, YTHDF2) in OP.
• Defined two distinct m6A modification patterns and immune phenotypes.
• Selected METTL4, HIRA, MATN4, and YTHDF2 as potential biomarkers with a validated nomogram.
• Confirmed HIRA downregulation in OP PBMCs and bone tissue, linked to immune dysregulation.

Conclusions:

• Established a potential m6A-related biomarker signature for OP.
• Provided multi-level evidence for HIRA as a consistently downregulated biomarker in OP.
• Linked epigenetic modification via m6A to immune dysregulation in osteoporosis pathogenesis.