AUTHOR=Delsmann Maximilian M. , Peichl Jonathan , Yorgan Timur A. , Beil Frank Timo , Amling Michael , Demay Marie B. , Rolvien Tim 

TITLE=Prevention of Hypomineralization In Auditory Ossicles of Vitamin D Receptor (Vdr) Deficient Mice

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.901265

DOI=10.3389/fendo.2022.901265

ISSN=1664-2392

ABSTRACT=<p>Intact mineralization of the auditory ossicles - the smallest bones in the body - is essential for sound transmission in the middle ear, while ossicular hypomineralization is associated with conductive hearing loss. Here, we performed a high-resolution analysis of the ossicles in vitamin D receptor deficient mice (<italic>Vdr<sup>-/-</sup></italic>), which are characterized by hypocalcemia and skeletal mineralization defects, and investigated whether local hypomineralization can be prevented by feeding a calcium-rich rescue diet (<italic>Vdr<sup>-/- res</sup></italic>). In <italic>Vdr<sup>-/-</sup></italic> mice fed a regular diet (<italic>Vdr<sup>-/- reg</sup></italic>), quantitative backscattered electron imaging (qBEI) revealed an increased void volume (porosity, p&lt;0.0001) along with lower mean calcium content (CaMean, p=0.0008) and higher heterogeneity of mineralization (CaWidth, p=0.003) compared to WT mice. Furthermore, a higher osteoid volume per bone volume (OV/BV; p=0.0002) and a higher osteocyte lacunar area (Lc.Ar; p=0.01) were found in histomorphometric analysis in <italic>Vdr<sup>-/- reg</sup></italic> mice. In <italic>Vdr<sup>-/- res</sup></italic> mice, full rescue of OV/BV and Lc.Ar (both p&gt;0.05 vs. WT) and partial rescue of porosity and CaWidth (p=0.02 and p=0.04 vs. WT) were observed. Compared with <italic>Hyp</italic> mice, a model of X-linked hypophosphatemic rickets, <italic>Vdr<sup>-/- reg</sup></italic> mice showed a lower osteoid volume in the ossicles (p=0.0002), but similar values in the lumbar spine. These results are consistent with later postnatal impairment of mineral homeostasis in <italic>Vdr<sup>-/-</sup></italic> mice than in <italic>Hyp</italic> mice, underscoring the importance of intact mineral homeostasis for ossicle mineralization during development. In conclusion, we revealed a distinct phenotype of hypomineralization in the auditory ossicles of <italic>Vdr<sup>-/-</sup></italic> mice that can be partially prevented by a rescue diet. Since a positive effect of a calcium-rich diet on ossicular mineralization was demonstrated, our results open new treatment strategies for conductive hearing loss. Future studies should investigate the impact of improved ossicular mineralization on hearing function.</p>