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 in:The 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
Language:English
Published: United States 06.12.2021
Subjects:
Adult
Aged
Alendronate - pharmacology
Animals
Antibodies, Neutralizing - pharmacology
Cell Differentiation - genetics
Clonal Hematopoiesis - genetics
Clonal Hematopoiesis - physiology
DNA Methyltransferase 3A - genetics
DNA Methyltransferase 3A - metabolism
Female
Humans
Interleukins - immunology
Interleukins - metabolism
Male
Mice
Mice, Knockout
Middle Aged
Osteoclasts - pathology
Osteoporosis - blood
Osteoporosis - drug therapy
Osteoporosis - genetics
Osteoporosis - physiopathology
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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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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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20211872