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Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations

Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of...

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Autores principales: Cabral, Wayne A., Stephan, Chris, Terajima, Masahiko, Thaivalappil, Abhirami A., Blanchard, Owen, Tavarez, Urraca L., Narisu, Narisu, Yan, Tingfen, Wincovitch, Stephen M., Taga, Yuki, Yamauchi, Mitsuo, Kozloff, Kenneth M., Erdos, Michael R., Collins, Francis S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497813/
https://www.ncbi.nlm.nih.gov/pubmed/37365004
http://dx.doi.org/10.1111/acel.13903
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author Cabral, Wayne A.
Stephan, Chris
Terajima, Masahiko
Thaivalappil, Abhirami A.
Blanchard, Owen
Tavarez, Urraca L.
Narisu, Narisu
Yan, Tingfen
Wincovitch, Stephen M.
Taga, Yuki
Yamauchi, Mitsuo
Kozloff, Kenneth M.
Erdos, Michael R.
Collins, Francis S.
author_facet Cabral, Wayne A.
Stephan, Chris
Terajima, Masahiko
Thaivalappil, Abhirami A.
Blanchard, Owen
Tavarez, Urraca L.
Narisu, Narisu
Yan, Tingfen
Wincovitch, Stephen M.
Taga, Yuki
Yamauchi, Mitsuo
Kozloff, Kenneth M.
Erdos, Michael R.
Collins, Francis S.
author_sort Cabral, Wayne A.
collection PubMed
description Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic “progerin” protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna (G609G) knock‐in (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‐type and KI osteoclasts from marrow‐derived precursors was inhibited by KI osteoblast‐conditioned 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‐type, 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‐talk contribute to abnormal bone formation in HGPS mice.
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spelling pubmed-104978132023-09-14 Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations Cabral, Wayne A. Stephan, Chris Terajima, Masahiko Thaivalappil, Abhirami A. Blanchard, Owen Tavarez, Urraca L. Narisu, Narisu Yan, Tingfen Wincovitch, Stephen M. Taga, Yuki Yamauchi, Mitsuo Kozloff, Kenneth M. Erdos, Michael R. Collins, Francis S. Aging Cell Research Articles Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic “progerin” protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna (G609G) knock‐in (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‐type and KI osteoclasts from marrow‐derived precursors was inhibited by KI osteoblast‐conditioned 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‐type, 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‐talk contribute to abnormal bone formation in HGPS mice. John Wiley and Sons Inc. 2023-06-26 /pmc/articles/PMC10497813/ /pubmed/37365004 http://dx.doi.org/10.1111/acel.13903 Text en © 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Cabral, Wayne A.
Stephan, Chris
Terajima, Masahiko
Thaivalappil, Abhirami A.
Blanchard, Owen
Tavarez, Urraca L.
Narisu, Narisu
Yan, Tingfen
Wincovitch, Stephen M.
Taga, Yuki
Yamauchi, Mitsuo
Kozloff, Kenneth M.
Erdos, Michael R.
Collins, Francis S.
Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
title Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
title_full Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
title_fullStr Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
title_full_unstemmed Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
title_short Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
title_sort bone dysplasia in hutchinson‐gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497813/
https://www.ncbi.nlm.nih.gov/pubmed/37365004
http://dx.doi.org/10.1111/acel.13903
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