{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T19:24:51Z","timestamp":1757705091298,"version":"3.37.3"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T00:00:00Z","timestamp":1652140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR076747"],"award-info":[{"award-number":["AR076747"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR072987"],"award-info":[{"award-number":["AR072987"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Notch receptors are determinants of cell fate and function, and play an important role in the regulation of bone development and skeletal remodeling. Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with <jats:italic>NOTCH3<\/jats:italic> pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. LMS presents with neurological developmental abnormalities and bone loss. We created a mouse model (<jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup>) harboring a 6691TAATGA mutation in the <jats:italic>Notch3<\/jats:italic> locus, and heterozygous <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup> mice exhibit cancellous and cortical bone osteopenia. In the present work, we explored whether Notch3 antisense oligonucleotides (ASO) downregulate <jats:italic>Notch3<\/jats:italic> and have the potential to ameliorate the osteopenia of <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup> mice. Notch3 ASOs decreased the expression of <jats:italic>Notch3<\/jats:italic> wild type and <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>6691-TAATGA<\/jats:italic><\/jats:sup> mutant mRNA expressed by <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup> mice in osteoblast cultures without evidence of cellular toxicity. The effect was specific since ASOs did not downregulate <jats:italic>Notch1<\/jats:italic>, <jats:italic>Notch2<\/jats:italic> or <jats:italic>Notch4<\/jats:italic>. The expression of Notch3 wild type and <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>6691-TAATGA<\/jats:italic><\/jats:sup> mutant transcripts also was decreased in bone marrow stromal cells and osteocytes following exposure to Notch3 ASOs. <jats:italic>In vivo<\/jats:italic>, the subcutaneous administration of Notch3 ASOs at 25 to 50 mg\/Kg decreased <jats:italic>Notch3<\/jats:italic> mRNA in the liver, heart and bone. Microcomputed tomography demonstrated that the administration of Notch3 ASOs ameliorates the cortical osteopenia of <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup> mice, and ASOs decreased femoral cortical porosity and increased cortical thickness and bone volume. However, the administration of Notch3 ASOs did not ameliorate the cancellous bone osteopenia of <jats:italic>Notch<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup> mice. In conclusion, Notch3 ASOs downregulate <jats:italic>Notch3<\/jats:italic> expression in skeletal cells and their systemic administration ameliorates cortical osteopenia in <jats:italic>Notch3<\/jats:italic><jats:sup><jats:italic>em1Ecan<\/jats:italic><\/jats:sup> mice; as such ASOs may become useful strategies in the management of skeletal diseases affected by Notch gain-of-function.<\/jats:p>","DOI":"10.1371\/journal.pone.0268225","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T17:24:10Z","timestamp":1652203450000},"page":"e0268225","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Use of antisense oligonucleotides to target Notch3 in skeletal cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9154-952X","authenticated-orcid":true,"given":"Ernesto","family":"Canalis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6464-9584","authenticated-orcid":true,"given":"Michele","family":"Carrer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tabitha","family":"Eller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jungeun","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,5,10]]},"reference":[{"issue":"4","key":"pone.0268225.ref001","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1152\/physrev.00005.2017","article-title":"Notch Signaling in Development, Tissue Homeostasis, and Disease","volume":"97","author":"C Siebel","year":"2017","journal-title":"Physiol Rev"},{"issue":"3","key":"pone.0268225.ref002","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1210\/er.2016-1002","article-title":"Notch Signaling and the Skeleton","volume":"37","author":"S Zanotti","year":"2016","journal-title":"Endocr Rev"},{"issue":"12","key":"pone.0268225.ref003","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1007\/s00198-018-4694-3","article-title":"Notch in skeletal physiology and disease","volume":"29","author":"E. 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