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Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model

RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in RAS genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells...

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Autores principales: Nandi, Sayantan, Chennappan, Saravanakkumar, Andrasch, Yannik, Fidan, Miray, Engler, Melanie, Ahmad, Mubashir, Tuckermann, Jan P., Zenker, Martin, Cirstea, Ion Cristian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624175/
https://www.ncbi.nlm.nih.gov/pubmed/36330334
http://dx.doi.org/10.3389/fcell.2022.1000575
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author Nandi, Sayantan
Chennappan, Saravanakkumar
Andrasch, Yannik
Fidan, Miray
Engler, Melanie
Ahmad, Mubashir
Tuckermann, Jan P.
Zenker, Martin
Cirstea, Ion Cristian
author_facet Nandi, Sayantan
Chennappan, Saravanakkumar
Andrasch, Yannik
Fidan, Miray
Engler, Melanie
Ahmad, Mubashir
Tuckermann, Jan P.
Zenker, Martin
Cirstea, Ion Cristian
author_sort Nandi, Sayantan
collection PubMed
description RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in RAS genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific HRAS germline mutations. The majority of these mutations affect residues 12 and 13, the same sites as somatic oncogenic HRAS mutations. The hallmarks of the disease include congenital cardiac anomalies, impaired thriving and growth, neurocognitive impairments, distinctive craniofacial anomalies, and susceptibility to cancer. Adult patients often present signs of premature aging including reduced bone mineral density and osteoporosis. Using a CS mouse model harbouring a Hras G12V germline mutation, we aimed at determining whether this model recapitulates the patients’ bone phenotype and which bone cells are driving the phenotype when mutated. Our data revealed that Hras G12V mutation induces bone loss in mice at certain ages. In addition, we identified that bone loss correlated with an increased number of osteoclasts in vivo and Hras G12V mutations increased osteoclastogenesis in vitro. Last, but not least, mutant osteoclast differentiation was reduced by treatment in vitro with MEK and PI3K inhibitors, respectively. These results indicate that Hras is a novel regulator of bone homeostasis and an increased osteoclastogenesis due to Hras G12V mutation contributes to bone loss in the Costello syndrome.
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spelling pubmed-96241752022-11-02 Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model Nandi, Sayantan Chennappan, Saravanakkumar Andrasch, Yannik Fidan, Miray Engler, Melanie Ahmad, Mubashir Tuckermann, Jan P. Zenker, Martin Cirstea, Ion Cristian Front Cell Dev Biol Cell and Developmental Biology RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in RAS genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific HRAS germline mutations. The majority of these mutations affect residues 12 and 13, the same sites as somatic oncogenic HRAS mutations. The hallmarks of the disease include congenital cardiac anomalies, impaired thriving and growth, neurocognitive impairments, distinctive craniofacial anomalies, and susceptibility to cancer. Adult patients often present signs of premature aging including reduced bone mineral density and osteoporosis. Using a CS mouse model harbouring a Hras G12V germline mutation, we aimed at determining whether this model recapitulates the patients’ bone phenotype and which bone cells are driving the phenotype when mutated. Our data revealed that Hras G12V mutation induces bone loss in mice at certain ages. In addition, we identified that bone loss correlated with an increased number of osteoclasts in vivo and Hras G12V mutations increased osteoclastogenesis in vitro. Last, but not least, mutant osteoclast differentiation was reduced by treatment in vitro with MEK and PI3K inhibitors, respectively. These results indicate that Hras is a novel regulator of bone homeostasis and an increased osteoclastogenesis due to Hras G12V mutation contributes to bone loss in the Costello syndrome. Frontiers Media S.A. 2022-10-18 /pmc/articles/PMC9624175/ /pubmed/36330334 http://dx.doi.org/10.3389/fcell.2022.1000575 Text en Copyright © 2022 Nandi, Chennappan, Andrasch, Fidan, Engler, Ahmad, Tuckermann, Zenker and Cirstea. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Nandi, Sayantan
Chennappan, Saravanakkumar
Andrasch, Yannik
Fidan, Miray
Engler, Melanie
Ahmad, Mubashir
Tuckermann, Jan P.
Zenker, Martin
Cirstea, Ion Cristian
Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model
title Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model
title_full Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model
title_fullStr Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model
title_full_unstemmed Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model
title_short Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model
title_sort increased osteoclastogenesis contributes to bone loss in the costello syndrome hras g12v mouse model
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624175/
https://www.ncbi.nlm.nih.gov/pubmed/36330334
http://dx.doi.org/10.3389/fcell.2022.1000575
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