Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis
Open Access
- 26 October 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 218 (12)
- https://doi.org/10.1084/jem.20211872
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.Keywords
Funding Information
- National Institutes of Health (R01HL082945, P01CA108631, P50CA206963)
- Howard Hughes Medical Institute
- Edward P. Evans Foundation
- National Heart, Lung, and Blood Institute (5T32HL116324)
- Damon Runyon Cancer Research Foundation (PST-35-21)
- Edward P. Evans Foundation
- Knut and Alice Wallenberg Foundation (KAW 2017.0436)
- Damon Runyon Cancer Research Foundation
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041398)
- 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
- Génome Québec
- Public Health Agency of Canada
- McGill University
- Cancer Research UK (C18281/A29019)
- Fonds de Recherche Québec Santé
- Calcul Québec
- Compute Canada
- National Institutes of Health (R01DK116716)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR077768)
- Brigham Research Institute
- Burroughs Wellcome
- Foundation Leducq
- Ludwig Center for Cancer Stem Cell Research
- American Society of Hematology
- National Institutes of Health (DP2-HL157540)
This publication has 57 references indexed in Scilit:
- Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor functionJCI Insight, 2012
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesisNature Genetics, 2012
- Bone-Density Testing Interval and Transition to Osteoporosis in Older WomenThe New England Journal of Medicine, 2012
- Anti–IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone lossThe Journal of Experimental Medicine, 2011
- Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applicationsBioinformatics, 2011
- Robust relationship inference in genome-wide association studiesBioinformatics, 2010
- Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitroJournal of Cellular and Molecular Medicine, 2010
- Genome-scale DNA methylation maps of pluripotent and differentiated cellsNature, 2008
- FRAX™ and the assessment of fracture probability in men and women from the UKOsteoporosis International, 2008