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Deletion of the sodium/hydrogen exchanger 6 causes low bone volume in adult mice

Citation

Daniel, Fuster et al. (2021), Deletion of the sodium/hydrogen exchanger 6 causes low bone volume in adult mice, Dryad, Dataset, https://doi.org/10.5061/dryad.9w0vt4bdt

Abstract

The sodium/hydrogen exchanger 6 (NHE6) localizes to recycling endosomes, where it mediates endosomal alkalinization through K+/H+ exchange. Mutations in the SLC9A6 gene encoding NHE6 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 key role of NHE6 in osteoblast-mediated mineralization. The goal of this study was to explore the role of NHE6 in bone homeostasis. To this end, we studied the bone phenotype of NHE6 knock-out mice by microcomputed tomography, quantitative histomorphometry and complementary ex vivo and in vitro studies. We detected NHE6 transcript and protein in both differentiated osteoclasts and mineralizing osteoblasts. In vitro studies with osteoclasts and osteoblasts derived from NHE6 knock-out mice demonstrated normal osteoclast differentiation and osteoblast proliferation without an impairment in mineralization capacity. Microcomputed tomography and bone histomorphometry studies showed a significantly reduced bone volume and trabecular number as well as an increased trabecular space at lumbar vertebrae of 6 months old NHE6 knock-out mice. The bone degradation marker c-terminal telopeptides of type I collagen was unaltered in NHE6 knock-out mice. However, we observed a reduction of the bone formation marker procollagen type 1 N-terminal propeptide, and increased circulating sclerostin levels in NHE6 knock-out mice. Subsequent studies revealed a significant upregulation of sclerostin transcript expression in both primary calvarial cultures and femora derived from NHE6 knock-out mice. Thus, loss of NHE6 in mice causes an increase of sclerostin expression associated with reduced bone formation and low bone volume.

Methods

See detailed information in published manuscript (https://pubmed.ncbi.nlm.nih.gov/34508879/) and attached README file.

Usage Notes

See detailed information in attached README file.

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Award: 31003A_152829

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Award: 31003A_152829

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Award: National Center for Competence in Research (NCCR) TransCure