NDLI: Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis

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Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis

Content Provider	Scilit
Author	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, 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.
Copyright Year	2021
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.
Related Links	https://rupress.org/jem/article-pdf/218/12/e20211872/1424539/jem_20211872.pdf
DOI	10.1084/jem.20211872
Journal	The Journal of experimental medicine
Issue Number	12
Volume Number	218
Language	English
Publisher	Rockefeller University Press
Publisher Date	2021-10-26
Access Restriction	Open
Subject Keyword	Research and Experimental Medicine Hematopoietic Bone Mineral Density Bone Marrow Transcription Factors Dnmt3a Osteoporosis Somatic Sup Mutations Chromatin Journal: The Journal of experimental medicine (Vol- 218, Issue- 12)
Content Type	Text

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