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Abstract: TH-PO557

Deletion of the Proton Receptor OGR1 in the Osteoclast Impairs Metabolic Acidosis-Mediated Bone Resorption

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Krieger, Nancy S., University of Rochester, Rochester, New York, United States
  • Chen, Luojing, University of Rochester Medical Center, Rochester, New York, United States
  • Becker, Jennifer, University of Rochester Medical Center, Rochester, New York, United States
  • Chan, Michaela, University of Rochester, Rochester, New York, United States
  • Bushinsky, David A., University of Rochester Medical Center, Rochester, New York, United States
Background

Metabolic acidosis (Met) induces bone resorption. Using mice with a global deletion of OGR1 we demonstrated that loss of OGR1, a G protein-coupled H+ sensing receptor, impairs H+-induced bone resorption. OGR1 activity in both osteoblasts (OB) and osteoclasts (OC) was altered by Met. To determine if Met directly activates OGR1 in OC, rather than indirectly through the OB, we generated a conditional knockout with an osteoclast-specific deletion of OGR1 (OC-cKO). We tested the hypothesis that the lack of OC OGR1 would lead to increased bone mass in actively growing mice which generate large amounts of metabolic acid.

Methods

OC-cKO mice were generated from a LysM-cre mouse and OGR1flox/flox mouse. We examined bones from 3 month old female mice using micro-computed tomography (μCT) and immunohistochemistry. Mesenchymal stem cells (MSC) from femurs of OC-cKO and control (ctl) mice were differentiated to OC. Mature OC were detected by TRAP staining. Mature OCs grown on cover slips were incubated in neutral (pH 7.4) or Met (pH 7.1) medium for 45 min and then stained for NFATc1 to define active OCs.

Results

μCT demonstrated increased bone in OC-cKO (Bone Volume / Total Volume: 34.9±4.6 % (OC-cKO) vs 11.3±0.7 % (ctl); Trabecular (Tb) Thickness: 0.07±0.006 mm (OC-cKO) vs 0.05±0.001 mm (ctl); Tb. Number: 6.3±0.1/mm (OC-cKO) vs 4.3±0.1/mm (ctl); all p<0.05). TRAP staining of tibia sections indicated a decrease in OC number / bone surface from OC-cKO (4.6±0.7/mm (OC-cKO) vs 7.4±0.2/mm (ctl)) and OC surface area / bone surface (13.8±5.3% (OC-cKO) vs 26.6±2.2% (ctl)). We observed that OC derived from MSC of OC-cKO have less TRAP staining in OC / well (10.7±2.1 (OC-cKO) vs 38.9±9.7 (ctl)) and decreased OC surface area (mm2/well: 0.05±0.01 (OC-cKO) vs 0.19±0.02 (ctl)). OC-cKO OC in response to Met had decreased nuclear translocation of NFATc1, a master transcriptional regulator of OC differentiation and proliferation, compared to ctl (17.0±2.6% (OC-cKO) vs 29.7±3.3% (ctl) p<0.05) but no difference at pH 7.4.

Conclusion

Our results indicate that OC OGR1 is directly regulated by Met and important in acid-induced bone resorption. Characterization of the direct role of OGR1 in acid-induced bone resorption may assist in understanding bone loss associated with the metabolic acidosis in patients with chronic kidney disease.

Funding

  • Private Foundation Support