Conductive Hearing Loss in the Hyp Mouse Model of X-Linked Hypophosphatemia Is Accompanied by Hypomineralization of the Auditory Ossicles.
ANIMAL MODELS
BONE MATRIX
CELL/TISSUE SIGNALING - ENDOCRINE PATHWAYS
GENETIC ANIMAL MODELS
MATRIX MINERALIZATION
PTH/Vit D/FGF23
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
27
08
2021
received:
06
04
2021
accepted:
13
09
2021
pubmed:
16
9
2021
medline:
24
12
2021
entrez:
15
9
2021
Statut:
ppublish
Résumé
X-linked hypophosphatemia (XLH) is a hereditary musculoskeletal disorder caused by loss-of-function mutations in the PHEX gene. In XLH, increased circulating fibroblast growth factor 23 (FGF23) levels cause renal phosphate wasting and low concentrations of 1,25-dihydroxyvitamin D, leading to an early clinical manifestation of rickets. Importantly, hearing loss is commonly observed in XLH patients. We present here data from two XLH patients with marked conductive hearing loss. To decipher the underlying pathophysiology of hearing loss in XLH, we utilized the Hyp mouse model of XLH and measured auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) to functionally assess hearing. As evidenced by the increased ABR/DPOAE threshold shifts in the mid-frequency range, these measurements indicated a predominantly conductive hearing loss in Hyp mice compared to wild-type (WT) mice. Therefore, we carried out an in-depth histomorphometric and scanning electron microscopic analysis of the auditory ossicles. Quantitative backscattered electron imaging (qBEI) indicated a severe hypomineralization of the ossicles in Hyp mice, evidenced by lower calcium content (CaMean) and higher void volume (ie, porosity) compared to WT mice. Histologically, voids correlated with unmineralized bone (ie, osteoid), and the osteoid volume per bone volume (OV/BV) was markedly higher in Hyp mice than WT mice. The density of osteocyte lacunae was lower in Hyp mice than in WT mice, whereas osteocyte lacunae were enlarged. Taken together, our findings highlight the importance of ossicular mineralization for hearing conduction and point toward the potential benefit of improving mineralization to prevent hearing loss in XLH. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Identifiants
pubmed: 34523743
doi: 10.1002/jbmr.4443
pmc: PMC8688200
mid: NIHMS1740572
doi:
Substances chimiques
Fibroblast Growth Factor-23
7Q7P4S7RRE
PHEX Phosphate Regulating Neutral Endopeptidase
EC 3.4.24.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2317-2328Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR072650
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC015824
Pays : United States
Organisme : NIH HHS
ID : R01-AR072650-01
Pays : United States
Organisme : NIH HHS
ID : R01-DC015824
Pays : United States
Informations de copyright
© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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