Kidney Week

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

• Novel Approaches to Mineral and Bone Metabolism
  October 22, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

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

Daniela Hanke, PhD



Daniela Hanke finished her PhD in the field of Bone research at the University of Bern in Switzerland in the fall of 2020. Her dissertation was titled “The role of sodium/proton exchangers NHEs in bone homeostasis” and supervised by Professor Daniel Fuster. Her interests include the current research in basic bone biology and treatment of bone-related disease.

• Albano, Giuseppe, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Giuseppe Albano,

• Anderegg, Manuel Andreas, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Manuel Andreas Anderegg,

• Fuster, Daniel G., Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Daniel G. Fuster,

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.