A trans-eQTL network regulates osteoclast multinucleation and bone mass.

Area of Science:

• Genetics
• Molecular Biology
• Skeletal Biology

Background:

• Understanding cell-type-specific regulatory networks is crucial for linking genetic variation to phenotype.
• Osteoclasts are a valuable model for studying co-regulated genes due to their role in skeletal traits.

Purpose of the Study:

• To investigate the functional role of the macrophage multinucleation network (MMnet) in regulating bone mass and osteoclast activity.
• To determine if MMnet genes, enriched for GWAS variants, contribute to bone-related phenotypes.

Main Methods:

• Utilized a trans-regulated gene network (MMnet) enriched for GWAS variants associated with bone phenotypes.
• Generated global and myeloid-specific knockout mice for MMnet genes (e.g., Bcat1, Pik3cb, Slc40a1).
• Assessed bone phenotypes in mice and correlated findings with human osteoclast function.

Main Results:

• Identified the MMnet hub gene Bcat1 and seven other MMnet genes as regulators of bone function.
• Observed abnormal bone phenotypes in global and myeloid-specific knockout mice.
• Demonstrated opposing effects of MMnet genes on mouse bone mass and human osteoclast activity, with strong correlation.

Conclusions:

• The MMnet is a functionally conserved network regulating osteoclast multinucleation and bone mass.
• MMnet genes provide a mechanistic link between genetic variation and skeletal phenotypes.
• This network offers a model for interrogating gene-phenotype relationships in bone biology.