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

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.