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Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts

The function of osteoclasts (OCs), multinucleated giant cells (MGCs) of the monocytic lineage, is bone resorption. To resorb bone, OCs form podosomes. These are actin-rich adhesive structures that pattern into rings that drive OC migration and into “sealing-zones” (SZs) that confine the resorption l...

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Autores principales: Georgess, Dan, Mazzorana, Marlène, Terrado, José, Delprat, Christine, Chamot, Christophe, Guasch, Rosa M., Pérez-Roger, Ignacio, Jurdic, Pierre, Machuca-Gayet, Irma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907278/
https://www.ncbi.nlm.nih.gov/pubmed/24284899
http://dx.doi.org/10.1091/mbc.E13-07-0363
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author Georgess, Dan
Mazzorana, Marlène
Terrado, José
Delprat, Christine
Chamot, Christophe
Guasch, Rosa M.
Pérez-Roger, Ignacio
Jurdic, Pierre
Machuca-Gayet, Irma
author_facet Georgess, Dan
Mazzorana, Marlène
Terrado, José
Delprat, Christine
Chamot, Christophe
Guasch, Rosa M.
Pérez-Roger, Ignacio
Jurdic, Pierre
Machuca-Gayet, Irma
author_sort Georgess, Dan
collection PubMed
description The function of osteoclasts (OCs), multinucleated giant cells (MGCs) of the monocytic lineage, is bone resorption. To resorb bone, OCs form podosomes. These are actin-rich adhesive structures that pattern into rings that drive OC migration and into “sealing-zones” (SZs) that confine the resorption lacuna. Although changes in actin dynamics during podosome patterning have been documented, the mechanisms that regulate these changes are largely unknown. From human monocytic precursors, we differentiated MGCs that express OC degradation enzymes but are unable to resorb the mineral matrix. We demonstrated that, despite exhibiting bona fide podosomes, these cells presented dysfunctional SZs. We then performed two-step differential transcriptomic profiling of bone-resorbing OCs versus nonresorbing MGCs to generate a list of genes implicated in bone resorption. From this list of candidate genes, we investigated the role of Rho/Rnd3. Using primary RhoE-deficient OCs, we demonstrated that RhoE is indispensable for OC migration and bone resorption by maintaining fast actin turnover in podosomes. We further showed that RhoE activates podosome component cofilin by inhibiting its Rock-mediated phosphorylation. We conclude that the RhoE-Rock-cofilin pathway, by promoting podosome dynamics and patterning, is central for OC migration, SZ formation, and, ultimately, bone resorption.
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spelling pubmed-39072782014-04-16 Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts Georgess, Dan Mazzorana, Marlène Terrado, José Delprat, Christine Chamot, Christophe Guasch, Rosa M. Pérez-Roger, Ignacio Jurdic, Pierre Machuca-Gayet, Irma Mol Biol Cell Articles The function of osteoclasts (OCs), multinucleated giant cells (MGCs) of the monocytic lineage, is bone resorption. To resorb bone, OCs form podosomes. These are actin-rich adhesive structures that pattern into rings that drive OC migration and into “sealing-zones” (SZs) that confine the resorption lacuna. Although changes in actin dynamics during podosome patterning have been documented, the mechanisms that regulate these changes are largely unknown. From human monocytic precursors, we differentiated MGCs that express OC degradation enzymes but are unable to resorb the mineral matrix. We demonstrated that, despite exhibiting bona fide podosomes, these cells presented dysfunctional SZs. We then performed two-step differential transcriptomic profiling of bone-resorbing OCs versus nonresorbing MGCs to generate a list of genes implicated in bone resorption. From this list of candidate genes, we investigated the role of Rho/Rnd3. Using primary RhoE-deficient OCs, we demonstrated that RhoE is indispensable for OC migration and bone resorption by maintaining fast actin turnover in podosomes. We further showed that RhoE activates podosome component cofilin by inhibiting its Rock-mediated phosphorylation. We conclude that the RhoE-Rock-cofilin pathway, by promoting podosome dynamics and patterning, is central for OC migration, SZ formation, and, ultimately, bone resorption. The American Society for Cell Biology 2014-02-01 /pmc/articles/PMC3907278/ /pubmed/24284899 http://dx.doi.org/10.1091/mbc.E13-07-0363 Text en © 2014 Georgess et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Georgess, Dan
Mazzorana, Marlène
Terrado, José
Delprat, Christine
Chamot, Christophe
Guasch, Rosa M.
Pérez-Roger, Ignacio
Jurdic, Pierre
Machuca-Gayet, Irma
Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts
title Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts
title_full Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts
title_fullStr Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts
title_full_unstemmed Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts
title_short Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts
title_sort comparative transcriptomics reveals rhoe as a novel regulator of actin dynamics in bone-resorbing osteoclasts
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907278/
https://www.ncbi.nlm.nih.gov/pubmed/24284899
http://dx.doi.org/10.1091/mbc.E13-07-0363
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