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Abstract: PO0334

Response of Bone to Acid: Effect of Deletion of the Proton Receptor OGR1 in the Osteoblast

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

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

Metabolic acidosis induces bone resorption by inhibiting osteoblast (OB) bone formation and stimulating osteoclast (OC) bone resorption. Mice generate large amounts of endogenous acid and we have shown that OGR1 is the proton (H+) receptor in bone and is stimulated by this endogenous acid. Mice with a global deletion of OGR1 have increased bone density which appears due to increased bone formation. There is communication between OB and OC and OGR1 is present in both. To determine if the response of OGR1 in the OB is independent of a response in OC, we generated a conditional knockout with an osteoblast-specific deletion of OGR1 (OB-cKO).

Methods

OB-cKO mice were generated from a col1a-cre mouse and an OGR1flox/flox mouse. We examined bones from 3 month old female mice using micro-computed tomography (µCT) and immunohistochemistry. Bone marrow mesenchymal stem cells (BMSC) from femurs of OB-cKO and wild type (WT) mice were differentiated to OB. Mineralization was detected with alizarin red and gene expression was analyzed by QPCR. All indicated changes are significant (p<0.05).

Results

Immunofluorescent staining of OGR1 in differentiated OB from BMSC confirmed the absence of OGR1 in OB-cKO cells compared to WT. μCT demonstrated an increase in tibia cortical bone area (0.76±0.01 vs 0.71±0.01 mm2), but no change in femoral cortical bone in OB-cKO compared to WT. Femoral trabecular bone was decreased (8.64±1.03 vs 11.81±0.70 %BV/TV), but there was no change in tibia trabecular bone. Alizarin red staining of differentiated BMSC showed greater mineralization of OB from OB-cKO mice compared to WT (5.14±0.02 vs 4.39±0.03 relative intensity). Relative gene expression of col1a (1.53±0.15 vs 0.88±0.10), osteocalcin (1.79±0.05 vs 1.13±0.18) and RANKL (2.89±0.48 vs 1.11±0.21) was higher in differentiated BMSC from OB-cKO mice compared to WT cells.

Conclusion

Our results demonstrate that specific loss of OB OGR1 alters the response of bone to endogenous acid on bone content, in vitro mineralization and gene expression compared to WT, indicating that the response of OGR1 in the OB is independent of the response in OC. 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

  • NIDDK Support