{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:56:58Z","timestamp":1793131018965,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AR069620"],"award-info":[{"award-number":["AR069620"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OD17979"],"award-info":[{"award-number":["OD17979"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hutchinson\u2010Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C\u2009&gt;\u2009T (p.G608G) mutation in the gene encoding lamin A (<jats:italic>LMNA<\/jats:italic>), which activates a cryptic splice donor site resulting in production of the toxic \u201cprogerin\u201d protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the <jats:italic>Lmna<\/jats:italic><jats:sup>G609G<\/jats:sup> knock\u2010in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild\u2010type and KI osteoclasts from marrow\u2010derived precursors was inhibited by KI osteoblast\u2010conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild\u2010type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross\u2010talk contribute to abnormal bone formation in HGPS mice.<\/jats:p>","DOI":"10.1111\/acel.13903","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T01:19:21Z","timestamp":1687828761000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Bone dysplasia in <scp>Hutchinson\u2010Gilford<\/scp> progeria syndrome is associated with dysregulated differentiation and function of bone cell populations"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0563-5289","authenticated-orcid":false,"given":"Wayne A.","family":"Cabral","sequence":"first","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Stephan","sequence":"additional","affiliation":[{"name":"Departments of Orthopedic Surgery and Biomedical Engineering University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Terajima","sequence":"additional","affiliation":[{"name":"Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7715-1611","authenticated-orcid":false,"given":"Abhirami A.","family":"Thaivalappil","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Departments of Orthopedic Surgery and Biomedical Engineering University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urraca L.","family":"Tavarez","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-1156","authenticated-orcid":false,"given":"Narisu","family":"Narisu","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingfen","family":"Yan","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen\u00a0M.","family":"Wincovitch","sequence":"additional","affiliation":[{"name":"Cytogenetics and Microscopy Core National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9100-758X","authenticated-orcid":false,"given":"Yuki","family":"Taga","sequence":"additional","affiliation":[{"name":"Nippi Research Institute of Biomatrix  Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M.","family":"Kozloff","sequence":"additional","affiliation":[{"name":"Departments of Orthopedic Surgery and Biomedical Engineering University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Erdos","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis S.","family":"Collins","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research National Human Genome Research Institute, NIH  Bethesda Maryland 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