{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kim PG"],"funding":["McGill","Cancer Research UK","Howard Hughes Medical Institute","NHLBI NIH HHS","Knut and Alice Wallenberg Foundation","National Heart, Lung, and Blood Institute","American Society of Hematology","Compute Canada","National Institutes of Health","Canadian Institutes of Health Research","Calcul Québec","Public Health Agency of Canada","Burroughs Wellcome","Deutsche Forschungsgemeinschaft","Fonds de Recherche Québec Santé","Jewish General Hospital Foundation","NIAMS NIH HHS","Damon Runyon Cancer Research Foundation","Edward P. Evans Foundation","NIH HHS","National Institute of Arthritis and Musculoskeletal and Skin Diseases","Ludwig Center for Cancer Stem Cell Research","Brigham Research Institute","McGill University","Canadian Foundation for Innovation","Foundation Leducq","NIDDK NIH HHS","Medical Research Council","NCI NIH HHS","Genome Québec","Lady Davis Institute"],"pagination":["e20211872"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8552148"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["218(12)"],"pubmed_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."],"journal":["The Journal of experimental medicine"],"pubmed_title":["Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis."],"pmcid":["PMC8552148"],"funding_grant_id":["409511","R01HL082945","P01 CA108631","R21AR077768","PST-35-21","R01 AR041398","365825","P50 CA206963","P01 CA066996","KAW 2017.0436","MI4","C18281/A29019","MC_QA137853","DP2-HL157540","100558","R35 CA253125","MC_PC_17228","DP2 HL157540","T32 HL116324","5T32HL116324","R01 HL082945","R21 AR077768","R01 DK116716","R01DK116716","R01AR041398","MC_UU_12013/4","P50CA206963","P01CA108631","AG252/1-1"],"pubmed_authors":["Griffin G","Kiel DP","Wong WJ","Ebert BL","Slabicki M","Pirruccello J","Evans DM","Shin WJ","Richards JB","Gibson CJ","Charles JF","Uddin MM","Lin AE","Sekar A","Natarajan P","Wein MN","Bick A","Kemp JP","Shkolnik V","Brooks DJ","Tsai JM","Jaiswal S","McConkey M","Cohen DN","Agrawal M","Bouxsein ML","Niroula A","Kim PG"],"additional_accession":[]},"is_claimable":false,"name":"Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.","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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Dec","modification":"2026-07-09T10:36:56.37Z","creation":"2025-02-19T04:04:49.775Z"},"accession":"S-EPMC8552148","cross_references":{"pubmed":["34698806"],"doi":["10.1084/jem.20211872"]}}