{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:33:58Z","timestamp":1780500838850,"version":"3.54.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR080416"],"award-info":[{"award-number":["R01AR080416"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["OH324\/2-1"],"award-info":[{"award-number":["OH324\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["RO 5925\/5-1"],"award-info":[{"award-number":["RO 5925\/5-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u00a0wk. In untreated Enpp1-deficient mice, we found elevated hearing thresholds at stimulus frequencies of 8, 16, and 32\u00a0kHz, 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.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf082","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T04:06:14Z","timestamp":1749614774000},"page":"1077-1086","source":"Crossref","is-referenced-by-count":1,"title":["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"],"prefix":"10.1093","volume":"40","author":[{"given":"Ana","family":"Ocokoljic","sequence":"first","affiliation":[{"name":"Division of Orthopaedics, Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf , 20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"von Kroge","sequence":"additional","affiliation":[{"name":"Division of Orthopaedics, Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf , 20246 Hamburg ,","place":["Germany"]},{"name":"Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R","family":"Stabach","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Busse","sequence":"additional","affiliation":[{"name":"Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Weise","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Oheim","sequence":"additional","affiliation":[{"name":"Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Rolvien","sequence":"additional","affiliation":[{"name":"Division of Orthopaedics, Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf , 20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demetrios T","family":"Braddock","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine , New Haven, CT 06510 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"issue":"4","key":"2025090306421112600_ref1","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/S0002-9440(10)63208-7","article-title":"Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders","volume":"164","author":"Harmey","year":"2004","journal-title":"Am J Pathol"},{"issue":"5","key":"2025090306421112600_ref2","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1002\/jbmr.4254","article-title":"Response of the ENPP1-deficient skeletal phenotype to oral phosphate supplementation and\/or enzyme replacement therapy: comparative studies in humans and mice","volume":"36","author":"Ferreira","year":"2021","journal-title":"J Bone Miner Res"},{"issue":"2","key":"2025090306421112600_ref3","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1161\/CIRCGENETICS.108.797704","article-title":"Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy","volume":"1","author":"Rutsch","year":"2008","journal-title":"Circ Cardiovasc Genet"},{"issue":"9","key":"2025090306421112600_ref4","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1002\/jbmr.4640","article-title":"Catalysis-independent ENPP1 protein signaling regulates mammalian bone mass","volume":"37","author":"Zimmerman","year":"2022","journal-title":"J Bone Miner 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