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...

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Published inThe Journal of experimental medicine Vol. 218; no. 12
Main Authors 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.
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 06.12.2021
Subjects
Adult
Aged
Alendronate - pharmacology
Animals
Antibodies, Neutralizing - pharmacology
Brief Definitive Report
Cell Differentiation - genetics
Clonal Hematopoiesis - genetics
Clonal Hematopoiesis - physiology
DNA Methyltransferase 3A - genetics
DNA Methyltransferase 3A - metabolism
Female
Hematopoiesis
Human Disease Genetics
Humans
Innate Immunity and Inflammation
Interleukins - immunology
Interleukins - metabolism
Male
Mice
Mice, Knockout
Middle Aged
Osteoclasts - pathology
Osteoporosis - blood
Osteoporosis - drug therapy
Osteoporosis - genetics
Osteoporosis - physiopathology
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Summary: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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Disclosures: A. Niroula reported grants from the Knut and Alice Wallenberg Foundation outside the submitted work. A. Bick reported personal fees from Foresite Labs outside the submitted work. J. Pirruccello reported personal fees from Maze Therapeutics outside the submitted work. M. Agrawal reported personal fees from German Accelerator Life Sciences outside the submitted work, and is the co-founder of and holds equity in iuvando Health. None of these are related to the submitted work. D.P. Kiel reported grants from Amgen, Radius Health, and Solarea Bio; and "other" from Solarea Bio, Pfizer, and Wolters Kluwer outside the submitted work. J.B. Richards reported personal fees from GlaxoSmithKline and Deerfield Capital; grants from Biogen and Eli Lilly; and non-financial support from 5 Prime Sciences outside the submitted work. J.B. Richards has served as an advisor to GlaxoSmithKline and Deerfield Capital. His institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the founder of 5 Prime Sciences. M.N. Wein reported grants from Radius Health and Galapagos NV, and "other" from Relation Therapeutics outside the submitted work. S. Jaiswal reported personal fees from AVRO Bio, Novartis, Genentech, and Foresite Labs outside the submitted work. P. Natarajan reported grants from Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Apple, AstraZeneca, Genentech, Novartis, Blackstone Life Sciences, and Foresite Labs; and "other" from Vertex outside the submitted work. B.L. Ebert reported grants from Celgene, Novartis, Deerfield, and Calico; and personal fees from Exo Therapeutics, Skyhawk Therapeutics, Neomorph Therapeutics, and TenSixteen Bio outside the submitted work. No other disclosures were reported.
ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20211872