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Abstract: TH-OR13

Deletion of the Sodium/Hydrogen Exchanger Isoform 6 in Mice Is Associated with an Age-Dependent Loss of Bone Volume

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hanke, Daniela, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • Albano, Giuseppe, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • Anderegg, Manuel Andreas, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • Fuster, Daniel G., Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Background

The sodium/hydrogen exchanger isoform 6 (NHE6) localizes to recycling endosomes, where it mediates endosomal alkalinization through K+/H+ exchange. NHE6 function in the endosome is essential for clathrin-mediated endocytosis, receptor recycling and endosomal signaling. Mutations in the SLC9A6 gene encoding the NHE6 isoform cause severe X-linked mental retardation, epilepsy, autism and corticobasal degeneration in humans. Patients with SLC9A6 mutations exhibit skeletal malformations, and a previous study suggested a role of NHE6 in osteoblast-mediated mineralization. The goal of this study was to explore the role of NHE6 in bone homeostasis

Methods

NHE6 expression, osteoclast differentiation and cell-mediated resorption were assessed in osteoclast precursor cells isolated from wild-type and NHE6 knock-out mice. In a next series of experiments, we used primary osteoblasts, extracted from calvaria of new-born mice, to study NHE6 expression, proliferation, and cell-mediated mineralization in vitro. To determine the impact of the in vitro findings on structural bone parameters, we performed high-resolution microcomputed tomography (μCT) studies on lumbar vertebrae of wild-type and NHE6 knock-out mice

Results

NHE6 transcript and protein are expressed in both primary osteoclasts and mineralizing osteoblasts. In vitro studies with osteoclasts and osteoblasts derived from NHE6 knock-out mice demonstrated normal osteoclast differentiation and osteoblast proliferation. However, NHE6-deficient osteoclasts exhibited a resorptive deficit, and the mineralization capacity was increased in osteoblasts lacking NHE6. Microcomputed tomography studies revealed a reduced bone volume at a single lumbar vertebral site (L4) but otherwise unaltered structural bone parameters in NHE6 knock-out mice compared to wild-type mice at 3 months of age. At 6 months of age, however, NHE6 knock-out mice displayed a significantly reduced bone volume and trabecular number as well as an increased trabecular space at all lumbar vertebrae studied (L3-L5) compared to wild-type mice

Conclusion

Thus, loss of NHE6 results in an age-dependent loss of bone volume in mice. The results of our in vitro studies argue against a direct bone cell-autonomous cause of the bone phenotype observed in NHE6 knock-out mice and suggest extraosseus factors as likely mediators

Funding

  • Government Support - Non-U.S.