在enpp1缺陷小鼠中,骨靶向酶替代疗法对听力损失的改善与纠正低矿化和听骨骨细胞特性有关。

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
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

摘要

听力损失在由ENPP1缺乏引起的情况下很常见,例如婴儿期全身性动脉钙化和常染色体隐性低磷血症2型佝偻病。从机制上讲,假设听骨矿化不良导致中耳声音传输受损。在这里,我们研究了酶替代疗法(ERT)是否能改善enpp1缺陷小鼠模型的听力损失,以及这是否与小骨的骨特性校正有关。为此,雄性Enpp1asj/asj小鼠接受可溶性或骨靶向的ENPP1-Fc ERT。在17周龄时,与未治疗的Enpp1asj/asj和野生型小鼠进行比较,评估听骨链的第一块骨——锤骨的听力功能和骨特性。在未治疗的enpp1缺陷小鼠中,我们发现在刺激频率为8 kHz、16 kHz和32 kHz时,听力阈值升高,表明听力普遍受损。可溶性ERT和骨靶向ERT均可部分或完全纠正Enpp1asj/asj小鼠的听力缺陷,表现为听觉脑干反应阈值的恢复,且具有剂量依赖性,骨靶向ERT的效果通常更强。这不仅与纠正血浆矿物质代谢标志物有关,而且还改善了基质矿化并恢复了锤骨的骨细胞特性。此外,我们首次在小鼠中证明了Enpp1asj/asj小鼠中存在矿化骨细胞腔隙,这一现象可以通过骨靶向但不溶性ERT来纠正,强调了靶向递送有效治疗的必要性。与人类骨细胞腔隙矿化(即微岩化)相反,腔隙内矿物质总体上比邻近骨骼矿化程度低。总之,我们的研究结果指出了纠正听骨矿化以预防ENPP1缺乏症听力损失的潜在益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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.

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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
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.
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