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GPR109A gene deletion ameliorates gonadectomy-induced bone loss in mice
Jin-Ran Chen1, Oxana P Lazarenko1, Michael L Blackburn1
1Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
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 β-catenin expression was higher in GPR109A-/- mice compared with their wild type littermates. Collectively, these data indicate that global GPR109A deletion ameliorates gonadectomy-induced bone loss through suppression of bone resorption.
Insights
Global GPR109A gene deletion protects against bone loss caused by sex steroid deficiency. This study shows GPR109A deletion in mice prevents bone resorption and preserves bone mass after ovariectomy and orchidectomy.
Area of Science:
- Bone Biology
- Endocrinology
- Pharmacology
Background:
- Sex steroid deficiency is a major cause of bone loss, characterized by increased bone resorption and uncertain bone formation.
- G protein-coupled receptor 109A (GPR109A) has been previously implicated in controlling osteoclastogenesis and bone resorption.
- Global GPR109A deletion was shown to decrease osteoclast resorption and increase bone mass.
Purpose of the Study:
- To investigate the role of GPR109A in gonadectomy-induced bone loss in female and male mice.
- To determine if GPR109A deletion can ameliorate bone loss following ovariectomy (OVX) and orchidectomy (ORX).
Main Methods:
- Utilized global GPR109A gene deletion mouse models.
- Employed ovariectomized (OVX) and orchidectomized (ORX) mouse models alongside sham-operated controls.
- Assessed bone mass and strength using micro-CT, peripheral quantitative CT (pQCT), and three-point bending tests.
- Measured bone remodeling markers including Cathepsin K, osteocalcin, and bone-specific alkaline phosphatase (ALP).
Main Results:
- Wild-type mice subjected to OVX or ORX exhibited significant decreases in bone volume, trabecular number, bone mineral density, and content.
- Global GPR109A deletion significantly ameliorated gonadectomy-induced bone loss in both male and female mice.
- In GPR109A-deficient female mice, bone mass and strength parameters remained largely unchanged between sham and OVX groups.
- GPR109A deletion suppressed bone resorption markers (Cathepsin K) and increased β-catenin expression, while wild-type mice showed increased resorption and formation markers post-gonadectomy.
Conclusions:
- Global GPR109A deletion effectively protects against bone loss induced by sex steroid deficiency.
- GPR109A plays a crucial role in mediating gonadectomy-induced bone loss, primarily through the suppression of bone resorption.
- Targeting GPR109A may represent a therapeutic strategy for preventing or treating bone loss associated with sex steroid deficiency.
