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Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis
Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analy...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552148/ https://www.ncbi.nlm.nih.gov/pubmed/34698806 http://dx.doi.org/10.1084/jem.20211872 |
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author | Kim, Peter Geon Niroula, Abhishek Shkolnik, Veronica McConkey, Marie Lin, Amy E. Słabicki, Mikołaj Kemp, John P. Bick, Alexander Gibson, Christopher J. Griffin, Gabriel Sekar, Aswin Brooks, Daniel J. Wong, Waihay J. Cohen, Drew N. Uddin, Md Mesbah Shin, Wesley J. Pirruccello, James Tsai, Jonathan M. Agrawal, Mridul Kiel, Douglas P. Bouxsein, Mary L. Richards, J. Brent Evans, David M. Wein, Marc N. Charles, Julia F. Jaiswal, Siddhartha Natarajan, Pradeep Ebert, Benjamin L. |
author_facet | Kim, Peter Geon Niroula, Abhishek Shkolnik, Veronica McConkey, Marie Lin, Amy E. Słabicki, Mikołaj Kemp, John P. Bick, Alexander Gibson, Christopher J. Griffin, Gabriel Sekar, Aswin Brooks, Daniel J. Wong, Waihay J. Cohen, Drew N. Uddin, Md Mesbah Shin, Wesley J. Pirruccello, James Tsai, Jonathan M. Agrawal, Mridul Kiel, Douglas P. Bouxsein, Mary L. Richards, J. Brent Evans, David M. Wein, Marc N. Charles, Julia F. Jaiswal, Siddhartha Natarajan, Pradeep Ebert, Benjamin L. |
author_sort | Kim, Peter Geon |
collection | PubMed |
description | Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a(−/−) demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB–mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation. |
format | Online Article Text |
id | pubmed-8552148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-85521482022-06-06 Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis Kim, Peter Geon Niroula, Abhishek Shkolnik, Veronica McConkey, Marie Lin, Amy E. Słabicki, Mikołaj Kemp, John P. Bick, Alexander Gibson, Christopher J. Griffin, Gabriel Sekar, Aswin Brooks, Daniel J. Wong, Waihay J. Cohen, Drew N. Uddin, Md Mesbah Shin, Wesley J. Pirruccello, James Tsai, Jonathan M. Agrawal, Mridul Kiel, Douglas P. Bouxsein, Mary L. Richards, J. Brent Evans, David M. Wein, Marc N. Charles, Julia F. Jaiswal, Siddhartha Natarajan, Pradeep Ebert, Benjamin L. J Exp Med Brief Definitive Report Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a(−/−) demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB–mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation. Rockefeller University Press 2021-10-26 /pmc/articles/PMC8552148/ /pubmed/34698806 http://dx.doi.org/10.1084/jem.20211872 Text en © 2021 Kim et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Report Kim, Peter Geon Niroula, Abhishek Shkolnik, Veronica McConkey, Marie Lin, Amy E. Słabicki, Mikołaj Kemp, John P. Bick, Alexander Gibson, Christopher J. Griffin, Gabriel Sekar, Aswin Brooks, Daniel J. Wong, Waihay J. Cohen, Drew N. Uddin, Md Mesbah Shin, Wesley J. Pirruccello, James Tsai, Jonathan M. Agrawal, Mridul Kiel, Douglas P. Bouxsein, Mary L. Richards, J. Brent Evans, David M. Wein, Marc N. Charles, Julia F. Jaiswal, Siddhartha Natarajan, Pradeep Ebert, Benjamin L. Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
title | Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
title_full | Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
title_fullStr | Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
title_full_unstemmed | Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
title_short | Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
title_sort | dnmt3a-mutated clonal hematopoiesis promotes osteoporosis |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552148/ https://www.ncbi.nlm.nih.gov/pubmed/34698806 http://dx.doi.org/10.1084/jem.20211872 |
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