GPR109A gene deletion ameliorates gonadectomy-induced bone loss in mice

Authors: CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC); LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC); BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Bone
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/12/2022
Publication Date: 4/27/2022
Citation: Chen, J., Lazarenko, O., Blackburn, M.L. 2022. GPR109A gene deletion ameliorates gonadectomy-induced bone loss in mice. Bone. https://doi.org/10.1016/j.bone.2022.116422.
DOI: https://doi.org/10.1016/j.bone.2022.116422

Interpretive Summary: Sex steroids are important bone-promoting hormones, and a reduction or loss of them leads to a reduction in bone quality and health. We have shown that GPR109A, a G protein coupled receptor, plays a role in the control of osteoclasts (cells that breakdown or increase resorption of bone) and that loss of GPR109A led to an increase in the amount of bone. Removal of the ovaries (ovariectomy (OVX)) in female mice and testes (orchidectomy (ORX)) in male mice are models for sex steroid bone loss. By using OVX and ORX mouse models in which GPR109A is deleted, we investigated the role of GPR109A in sex steroid-induced bone loss. Six month old GPR109A-deleted mice and wild type litter mates were allocated to a control group and OVX, or ORX for six weeks. When compared to wild type control mice, the wild type OVX and ORX groups had lower bone mass, including lower bone mineral density and content, while GPR109A-deleted control mice had significantly greater bone mass. Not only did deletion of GPR109A increase bone mass in the OVX and ORX groups compared to their controls, it restored the OVX/ORX-induced bone loss. We found significant changes in bone remodeling markers between wild type control and OVX groups, however; there changes were no changes in bone remodeling markers found between GPR109A-deleted control and OVX groups. These findings imply that deletion of GPR109A reduces bone loss caused by the reduction or loss of sex steroids by suppressing bone resorption.

Technical Abstract: Sex steroid deficiency plays critical roles in the pathophysiology of bone as the result of uncertain bone remodeling, i.e., increased bone resorption with equivocal bone formation. We have previously shown that GPR109A, a G protein coupled receptor, controls osteoclastogenesis and bone resorption, where global GPR109A deletion decreased osteoclast bone resorption and increased bone mass. Here, we used global GPR109A gene deletion, ovariectomized (OVX) and orchidectomized (ORX) mouse models to probe the role of GPR109A in gonadectomy-induced bone loss in female and male mice. Six months old GPR109A-/- mice and their wild type littermates were allocated to Sham or gonadectomized groups for six weeks. Using densitometric micro-CT confirmed by peripheral quantitative CT (pQCT) scans on tibia and spine, and three-point bending test on femur ex vivo, we found the bone volume, trabecular number, as well as bone mineral density and content in both trabecular and cortical sites were significantly decreased in wild type OVX and ORX compared with respective Sham groups. While bone mass in both male and female GPR109A-/- Sham groups were significantly higher compared with their respective wild type Sham groups, global GPR109A gene deletion ameliorated gonadectomy-induced bone loss. In GPR109A-/- females, most of bone mass and strength parameters measured by micro-CT, pQCT and three-point bending test were not different between Sham and OVX groups. In wild type but not in GPR109-/- mice, bone remodeling marker measurements indicated that both bone resorption (Cathepsin K) and bone formation (osteocalcin) markers were increased in gonadectomized mice compared to sham, with the exception of bone specific ALP, which was decreased in gonadectomized mice. Expression of bone resorption markers (Cathepsin K) were significantly lower, but ß-catenin expression was higher in GPR109A-/- mice compared with their wild type litter mates. Collectively, these data indicate that global GPR109A deletion ameliorates gonadectomy-induced bone loss through suppression of bone resorption.