However, it remains unknown whether dietary or bone-targeted treatments ameliorate ossicular hypomineralization and conductive hearing loss.

In the latter context, we and others have previously demonstrated that the integrity and especially bone mineralization of auditory ossicles is of decisive importance for sound transmission in the hearing process ( 9– 12). Nonetheless, extraskeletal complications such as dental problems or hearing loss are also recognized. Poor bone mineralization (i.e., rickets, osteomalacia) is primarily characterized by skeletal complications such as insufficiency fractures. In Vdr -/- mice fed a calcium-/phosphate-rich rescue diet from 16 days of age, normalized mineral ion homeostasis was observed with normal osteoid and tibial bone volume, showing that intestinal calcium absorption is a critical factor in mineral metabolism and bone mineralization ( 6, 8). Furthermore, the growth plates present a marked disorganization and a significant increase in the length of the hypertrophic chondrocyte layer ( 5, 6, 8). The calcium level stabilizes 30% below that of wildtype (WT) mice, while phosphate is increasingly eliminated via the kidney due to secondary hyperparathyroidism, resulting in hypophosphatemia ( 3, 5).Īltered calcium and phosphate metabolism lead to marked skeletal abnormalities such as severe osteomalacia with a 30-fold greater osteoid volume compared to control littermates, leading to a significant reduction of biomechanical properties and increased bone fragility ( 6, 7). After weaning, secondary hyperparathyroidism compensates for the reduced intestinal calcium absorption by PTH-mediated bone resorption however, the serum calcium level drops after about 4 weeks of age ( 3, 5). In the first 18 days of life, a non-saturable 1,25-dihydroxyvitamin D-independent mechanism maintains calcium absorption ( 4). The Vdr knockout mouse ( Vdr -/-), a model of hereditary vitamin D-dependent rickets type II, lacks vitamin D-dependent gene expression, resulting in impaired mineral ion homeostasis and related defects like rickets ( 2, 3). The vitamin D receptor (Vdr) is a calcitriol (1,25-dihydroxyvitamin D 3) binding nuclear receptor encoded by the Vdr gene that regulates gene transcription by binding to a vitamin D response element in the promoter region of certain genes ( 1). Future studies should investigate the impact of improved ossicular mineralization on hearing function. Since a positive effect of a calcium-rich diet on ossicular mineralization was demonstrated, our results open new treatment strategies for conductive hearing loss. In conclusion, we revealed a distinct phenotype of hypomineralization in the auditory ossicles of Vdr -/- mice that can be partially prevented by a rescue diet. These results are consistent with later postnatal impairment of mineral homeostasis in Vdr -/- mice than in Hyp mice, underscoring the importance of intact mineral homeostasis for ossicle mineralization during development. Compared with Hyp mice, a model of X-linked hypophosphatemic rickets, Vdr -/- reg mice showed a lower osteoid volume in the ossicles (p=0.0002), but similar values in the lumbar spine. WT) and partial rescue of porosity and CaWidth (p=0.02 and p=0.04 vs. In Vdr -/- mice fed a regular diet ( Vdr -/- reg), quantitative backscattered electron imaging (qBEI) revealed an increased void volume (porosity, p0.05 vs. Here, we performed a high-resolution analysis of the ossicles in vitamin D receptor deficient mice ( Vdr -/-), which are characterized by hypocalcemia and skeletal mineralization defects, and investigated whether local hypomineralization can be prevented by feeding a calcium-rich rescue diet ( Vdr -/- res). 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.

Auditory ossicles function