Conductive hearing loss in the Hyp mouse model of X-linked hypophosphatemia is accompanied by hypomineralization of the auditory ossicles
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Conductive hearing loss in the Hyp mouse model of X-linked hypophosphatemia is accompanied by hypomineralization of the auditory ossicles. / Delsmann, Maximilian M; Seist, Richard; Stürznickel, Julian; Schmidt, Felix N; Mansour, Amer; Kobelski, Margaret M; Broocks, Gabriel; Peichl, Jonathan; Oheim, Ralf; Praetorius, Mark; Schinke, Thorsten; Amling, Michael; Demay, Marie B; Stankovic, Konstantina M; Rolvien, Tim.
In: J BONE MINER RES, Vol. 36, No. 12, 12.2021, p. 2317-2328.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Conductive hearing loss in the Hyp mouse model of X-linked hypophosphatemia is accompanied by hypomineralization of the auditory ossicles
AU - Delsmann, Maximilian M
AU - Seist, Richard
AU - Stürznickel, Julian
AU - Schmidt, Felix N
AU - Mansour, Amer
AU - Kobelski, Margaret M
AU - Broocks, Gabriel
AU - Peichl, Jonathan
AU - Oheim, Ralf
AU - Praetorius, Mark
AU - Schinke, Thorsten
AU - Amling, Michael
AU - Demay, Marie B
AU - Stankovic, Konstantina M
AU - Rolvien, Tim
N1 - This article is protected by copyright. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - 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).
AB - 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).
U2 - 10.1002/jbmr.4443
DO - 10.1002/jbmr.4443
M3 - SCORING: Journal article
C2 - 34523743
VL - 36
SP - 2317
EP - 2328
JO - J BONE MINER RES
JF - J BONE MINER RES
SN - 0884-0431
IS - 12
ER -