Heme metabolism mediates RANKL-induced osteoclastogenesis via mitochondrial oxidative phosphorylation.

Summary

Heme biosynthesis is upregulated during RANKL-driven osteoclastogenesis, supporting mitochondrial function and elevated membrane potential. Genetic (Ferrochelatase silencing) and pharmacologic (N-methyl Protoporphyrin IX) inhibition of heme synthesis suppress osteoclast differentiation and protect against ovariectomy-induced bone loss, nominating heme metabolism as a druggable axis.

Key Findings

• RANKL-induced osteoclastogenesis elevates mitochondrial biogenesis and membrane potential.
• Heme synthesis/metabolism pathways are activated with a stepwise gene expression pattern.
• Ferrochelatase knockdown or NMPP inhibits osteoclast differentiation in a dose-dependent manner.
• Single-dose NMPP protects against ovariectomy-induced bone loss in mice.
• Human data suggest associations between heme-related genes and bone mineral density.

Clinical Implications

Positions heme biosynthesis as a therapeutic target for osteoporosis and other high-turnover bone diseases; supports development of selective heme-pathway inhibitors with bone-specific delivery.

Limitations

• Preclinical study; safety, off-target effects, and translational dosing of heme-pathway inhibitors are untested
• Small number of human donors for ex vivo validation

Future Directions

Develop selective, bone-targeted heme-pathway modulators; evaluate safety and efficacy in larger animal models and early-phase clinical trials; identify biomarkers for patient stratification.