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Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF

Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiatio...

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Autores principales: Stemig, Melissa, Astelford, Kristina, Emery, Ann, Cho, Jangyeun J., Allen, Ben, Huang, Tsang-hai, Gopalakrishnan, Rajaram, Mansky, Kim C., Jensen, Eric D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398560/
https://www.ncbi.nlm.nih.gov/pubmed/25875108
http://dx.doi.org/10.1371/journal.pone.0123843
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author Stemig, Melissa
Astelford, Kristina
Emery, Ann
Cho, Jangyeun J.
Allen, Ben
Huang, Tsang-hai
Gopalakrishnan, Rajaram
Mansky, Kim C.
Jensen, Eric D.
author_facet Stemig, Melissa
Astelford, Kristina
Emery, Ann
Cho, Jangyeun J.
Allen, Ben
Huang, Tsang-hai
Gopalakrishnan, Rajaram
Mansky, Kim C.
Jensen, Eric D.
author_sort Stemig, Melissa
collection PubMed
description Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiation and resorptive function. We recently reported that histone deacetylase 7 (HDAC7) binds to and represses the transcriptional activity of MITF in osteoclasts, and that loss of HDAC7 in vitro accelerated osteoclastogenesis. In the current study, we extend this initial observation by showing that conditional deletion of HDAC7 in osteoclasts of mice leads to an in vivo enhancement in osteoclast formation, associated with increased bone resorption and lower bone mass. Expression of multiple MITF target genes is increased in bone marrow derived osteoclast cultures from the HDAC7 knockout mice. Interestingly, multiple regions of the HDAC7 amino-terminus can bind to MITF or exert repressive activity. Moreover, mutation or deletion of the HDAC7 conserved deacetylase catalytic domain had little effect on repressive function. These observations identify HDAC7 in osteoclasts as an important molecular regulator of MITF activity and bone homeostasis, but also highlight a gap in our understanding of exactly how HDAC7 functions as a corepressor.
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spelling pubmed-43985602015-04-21 Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF Stemig, Melissa Astelford, Kristina Emery, Ann Cho, Jangyeun J. Allen, Ben Huang, Tsang-hai Gopalakrishnan, Rajaram Mansky, Kim C. Jensen, Eric D. PLoS One Research Article Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiation and resorptive function. We recently reported that histone deacetylase 7 (HDAC7) binds to and represses the transcriptional activity of MITF in osteoclasts, and that loss of HDAC7 in vitro accelerated osteoclastogenesis. In the current study, we extend this initial observation by showing that conditional deletion of HDAC7 in osteoclasts of mice leads to an in vivo enhancement in osteoclast formation, associated with increased bone resorption and lower bone mass. Expression of multiple MITF target genes is increased in bone marrow derived osteoclast cultures from the HDAC7 knockout mice. Interestingly, multiple regions of the HDAC7 amino-terminus can bind to MITF or exert repressive activity. Moreover, mutation or deletion of the HDAC7 conserved deacetylase catalytic domain had little effect on repressive function. These observations identify HDAC7 in osteoclasts as an important molecular regulator of MITF activity and bone homeostasis, but also highlight a gap in our understanding of exactly how HDAC7 functions as a corepressor. Public Library of Science 2015-04-15 /pmc/articles/PMC4398560/ /pubmed/25875108 http://dx.doi.org/10.1371/journal.pone.0123843 Text en © 2015 Stemig et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Stemig, Melissa
Astelford, Kristina
Emery, Ann
Cho, Jangyeun J.
Allen, Ben
Huang, Tsang-hai
Gopalakrishnan, Rajaram
Mansky, Kim C.
Jensen, Eric D.
Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF
title Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF
title_full Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF
title_fullStr Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF
title_full_unstemmed Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF
title_short Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF
title_sort deletion of histone deacetylase 7 in osteoclasts decreases bone mass in mice by interactions with mitf
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398560/
https://www.ncbi.nlm.nih.gov/pubmed/25875108
http://dx.doi.org/10.1371/journal.pone.0123843
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