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

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.