Sex dependent effects 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 increased trabecular bone in both tibia and vertebrae when compared to control genotypes (f/f, Cre⁺). However, at later time points (6 and 12 months), Cre⁺ males exhibited similar trabecular bone phenotypes compared to CKO mice. In contrast, female CKO mice displayed significantly increased trabecular bone at 6 and 12 months. Using three-point bending analysis it was found that only 12-month-old Cre⁺ and CKO male mice exhibited altered bone mechanical properties when compared to f/f mice, while for females no significant changes in bone mechanical properties were observed. These findings suggest that GPR109A regulates bone turnover pathways in a sex-specific manner.