Improvements in hearing loss with bone-targeted enzyme replacement therapy are associated with corrected hypomineralization and osteocyte properties of auditory ossicles in Enpp1-deficient mice.
Ana Ocokoljic, Shivani Srivastava, Simon von Kroge, Paul R Stabach, Björn Busse, Keith Weise, Ralf Oheim, Tim Rolvien, Demetrios T Braddock
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引用次数: 0
Abstract
Hearing loss is common in conditions caused by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency, such as generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2. Mechanistically, it is hypothesized that poor mineralization of the auditory ossicles leads to impaired sound transmission in the middle ear. Here we investigated whether enzyme replacement therapy (ERT) improves hearing loss in an Enpp1-deficient mouse model and whether this is associated with corrected bone properties in the ossicles. For this purpose, male Enpp1asj/asj mice were subjected to either a soluble or bone-targeted ERT of ENPP1-Fc. Hearing function and bone properties of the malleus, the first bone of the ossicular chain, were evaluated and compared to untreated Enpp1asj/asj and WT mice at the age of 17 wk. In untreated Enpp1-deficient mice, we found elevated hearing thresholds at stimulus frequencies of 8, 16, and 32 kHz, suggesting a generalized impairment of hearing. The hearing deficits observed in Enpp1asj/asj mice were partially or fully corrected by both soluble and bone-targeted ERT, as evidenced by the restoration of auditory brainstem response thresholds, with dose dependence and generally stronger effect of bone-targeted ERT. This was not only associated with corrected blood plasma markers of mineral metabolism but also improved matrix mineralization and restored osteocyte properties in the malleus. In addition, for the first time in mice, we were able to demonstrate the occurrence of mineralized osteocyte lacunae in Enpp1asj/asj mice, a phenomenon that was corrected by bone-targeted but not soluble ERT, underscoring the need for targeted delivery for effective treatment. In contrast to osteocyte lacunar mineralization in humans (ie, micropetrosis), the intra-lacunar mineral was overall less mineralized than the adjacent bone. In conclusion, our results point toward the potential benefit of correcting ossicular mineralization to prevent hearing loss in ENPP1 deficiency.
期刊介绍:
The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.