Sex-dependent effect of GPR109A gene deletion in myeloid cells on bone development in mice

TL;DR

Deleting the GPR109A gene in myeloid cells affects bone development differently in male and female mice.

Contribution

This study reveals a sex-specific role of GPR109A in myeloid cells for regulating bone resorption.

Findings

Male CKO mice showed improved bone parameters at 35 days but similar results to controls at later ages.

Female CKO mice had improved bone parameters at 6 and 12 months.

Female CKO mice showed increased Irf8 gene expression, which suppresses osteoclast formation.

Abstract

Blueberry metabolite-derived phenolic acids are thought to suppress bone resorption via interactions with the G protein-coupled receptor 109A (GPR109A). Previously, global GPR109A knockout (GPR109A
⁻/⁻
) mice exhibited increased bone mass and a diminished bone-protective response to phenolic acids. While GPR109A is highly expressed in osteoclast precursor macrophages, its role in bone development remains unclear. To address this, we generated a myeloid cell-specific GPR109A knockout (GPR109A
flox/flox
/LysM-Cre⁺; CKO) mouse model and assessed bone phenotypes in male and female mice at 35 days, 3 months, 6 months, and 12 months using µCT. At 35 days, CKO males showed significantly improved tibia and vertebrae µCT parameters compared to controls (f/f, Cre⁺). However, at later time points (6 and 12 months), Cre recombinase effects were observed, with Cre⁺ males exhibiting similar bone parameters to CKO mice. In contrast, female CKO mice displayed significantly improved µCT parameters at 6 and 12 months. Notably, 12-month-old Cre⁺ males exhibited altered bone mechanical properties, while females did not. Gene expression analysis revealed increased Interferon regulatory factor 8 (Irf8), an osteoclastogenesis suppressor, in female CKO mice. These findings suggest that GPR109A regulates bone resorption through osteoclastogenic pathways in a sex-specific manner.