{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:47:38Z","timestamp":1791528458281,"version":"4.3.4"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":1152,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":156,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["311723-GENEPAD"],"award-info":[{"award-number":["311723-GENEPAD"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G0800933\/87390"],"award-info":[{"award-number":["G0800933\/87390"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["060829\/Z\/00Z"],"award-info":[{"award-number":["060829\/Z\/00Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["311723\u2010GENEPAD"],"award-info":[{"award-number":["311723\u2010GENEPAD"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council Canada","doi-asserted-by":"publisher","award":["G0800933\/87390"],"award-info":[{"award-number":["G0800933\/87390"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["060829\/Z\/00Z"],"award-info":[{"award-number":["060829\/Z\/00Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor \u03baB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a75dup27\/\u2212) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27\/\u2212 animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a75dup27\/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. \u00a9 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..<\/jats:p>","DOI":"10.1002\/jbmr.4288","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T19:16:37Z","timestamp":1615922197000},"page":"1376-1386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Insertion Mutation in Tnfrsf11a Causes a Paget's Disease\u2013Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-5955","authenticated-orcid":false,"given":"Nerea","family":"Alonso","sequence":"first","affiliation":[{"name":"Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Wani","sequence":"additional","affiliation":[{"name":"Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Rose","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM) University of Edinburgh Edinburgh UK"},{"name":"Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob J.","family":"van't Hof","sequence":"additional","affiliation":[{"name":"Institute of Aging and Chronic Disease University of Liverpool Liverpool UK"},{"name":"Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2804-7586","authenticated-orcid":false,"given":"Stuart H.","family":"Ralston","sequence":"additional","affiliation":[{"name":"Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5916-5983","authenticated-orcid":false,"given":"Omar M.E.","family":"Albagha","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences Hamad Bin Khalifa University Doha Qatar"},{"name":"Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"issue":"8","key":"2024012713480930300_jbmr4288-bib-0001","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1359\/jbmr.2003.18.8.1381","article-title":"Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene","volume":"18","author":"Nakatsuka","year":"2003","journal-title":"J Bone Miner Res"},{"issue":"4","key":"2024012713480930300_jbmr4288-bib-0002","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s00223-008-9177-7","article-title":"Clinical and biochemical response of TNFRSF11A-mediated early-onset familial Paget disease to bisphosphonate therapy","volume":"83","author":"Riches","year":"2008","journal-title":"Calcif Tissue Int"},{"issue":"1","key":"2024012713480930300_jbmr4288-bib-0003","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/71667","article-title":"Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis","volume":"24","author":"Hughes","year":"2000","journal-title":"Nat Genet"},{"issue":"5","key":"2024012713480930300_jbmr4288-bib-0004","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00223-019-00520-5","article-title":"Rare inherited forms of Paget's disease and related syndromes","volume":"104","author":"Ralston","year":"2019","journal-title":"Calcif Tissue Int"},{"issue":"8","key":"2024012713480930300_jbmr4288-bib-0005","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1002\/jbmr.399","article-title":"Signal peptide mutations in RANK prevent downstream activation of NF-kappaB","volume":"26","author":"Crockett","year":"2011","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2024012713480930300_jbmr4288-bib-0006","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0022-2836(85)90046-4","article-title":"Signal sequences. 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