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Cited by 164Bone Metabolism and DiseasesBone health and osteoporosis researchAcute Myeloid Leukemia Research

Dnmt3a -mutated clonal hematopoiesis promotes osteoporosis

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Kim, Peter Geon, Niroula, Abhishek, Shkolnik, Veronica, McConkey, Marie, Lin, Amy E., Słabicki, Mikołaj, Kemp, John P., Bick, Alexander +20 more·2021·Journal of Experimental Medicine
DOI 10.1084/jem.20211872PMC PMC8552148
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Abstract

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.

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  • Murine Dnmt3a mutant hematopoiesis promotes osteoporosis and bone loss through increased osteoclastogenesis that can be reversed by bisphosphonate treatment.

    “murine Dnmt3a mutant hematopoiesis has been shown promote osteoporosis and bone loss through increased osteoclastogenesis that could be reversed by bisphosphonate treatment [40].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [40]

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Cited by

Sorted by citations

Authors
Kim, P. G., Niroula, A., Shkolnik, V., McConkey, M., Lin, A. E., Słabicki, M., Kemp, J. P., Bick, A., Gibson, C. J., Griffin, G., Sekar, A., Brooks, D. J., Wong, W. J., Cohen, D. N., Uddin, M. M., Shin, W. J., Pirruccello, J., Tsai, J. M., Agrawal, M., Kiel, D. P., Bouxsein, M. L., Richards, J. B., Evans, D. M., Wein, M. N., Charles, J. F., Jaiswal, S., Natarajan, P., & Ebert, B. L.
Affiliations
  • Broad Institute (US)
  • Dana-Farber Cancer Institute (US)
  • Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 1
  • The University of Queensland (AU)
  • Vanderbilt University (US)
  • Beth Israel Deaconess Medical Center (US)
  • Harvard University (US)
  • King's College London (GB)
  • Brigham and Women's Hospital (US)
  • Stanford Medicine (US)
Corresponding author
Ebert, Benjamin L.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2021-10-26
Volume
218
Issue
12
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20211872
PMC
PMC8552148
OpenAlex
W3208200442
Cited by
164
References
5
Citations by year
2026: 24 · 2025: 34 · 2024: 34 · 2023: 35 · 2022: 34 · 2021: 2 · 2020: 1
FWCI
8.24
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (R01HL082945, P01CA108631, P50CA206963, R01DK116716, DP2-HL157540)
  • Howard Hughes Medical Institute
  • Edward P. Evans Foundation
  • National Heart, Lung, and Blood Institute (5T32HL116324)
  • Damon Runyon Cancer Research Foundation (PST-35-21)
  • Knut and Alice Wallenberg Foundation (KAW 2017.0436)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041398, R21AR077768)
  • Deutsche Forschungsgemeinschaft (AG252/1-1)
  • Canadian Institutes of Health Research (365825, 409511, 100558)
  • McGill (MI4)
  • Lady Davis Institute
  • Jewish General Hospital Foundation
  • Canadian Foundation for Innovation
  • Cancer Research UK (C18281/A29019)
  • Genome Québec
  • Public Health Agency of Canada
  • McGill University
  • Fonds de Recherche Québec Santé
  • Calcul Québec
  • Compute Canada
  • Brigham Research Institute
  • Burroughs Wellcome
  • Foundation Leducq
  • Ludwig Center for Cancer Stem Cell Research
  • American Society of Hematology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
DNMT3A, clonal hematopoiesis of indeterminate potential, osteoporosis, osteoclastogenesis, bone loss, bone marrow inflammation, DNA methylation, demethylation, chromatin accessibility, IL-20, macrophages, alendronate, bone mineral density, somatic mutations
MeSH terms
Clonal Hematopoiesis, DNA Methyltransferase 3A, Adult, Aged, Animals, Cell Differentiation, Female, Humans, Interleukins, Male, Middle Aged, Osteoclasts, Osteoporosis, Mice, Knockout, Alendronate, Mice, Antibodies, Neutralizing

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