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<p>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<sup>−/−</sup>) 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<sup>flox/flox</sup>/LysM-Cre⁺; CKO) mouse model and assessed bone phenotypes in male and female mice at 35&#xa0;days, 3&#xa0;months, 6&#xa0;months, and 12&#xa0;months using µCT. At 35&#xa0;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&#xa0;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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • Perry C. Caviness,
  • Oxana P. Lazarenko,
  • Michael L. Blackburn,
  • Jin-Ran Chen

摘要

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 (GPR109Aflox/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.