Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.
Peter Geon KimAbhishek NiroulaVeronica ShkolnikMarie McConkeyAmy E LinMikołaj SłabickiJohn P KempAlexander G BickChristopher J GibsonGabriel K GriffinAswin SekarDaniel J BrooksWaihay J WongDrew Nathaniel CohenM D Mesbah UddinWesley J ShinJames Paul PirruccelloJonathan M TsaiMridul AgrawalDouglas P KielMary L BouxseinJohn Brent RichardsDavid M EvansMarc N WeinJulia Forgan-Farnam CharlesSiddhartha JaiswalPradeep NatarajanBenjamin L EbertPublished in: The Journal of experimental medicine (2021)
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.
Keyphrases
- bone mineral density
- bone loss
- postmenopausal women
- dna methylation
- bone marrow
- induced apoptosis
- body composition
- genome wide
- oxidative stress
- copy number
- transcription factor
- high throughput
- cell cycle arrest
- circulating tumor cells
- gene expression
- wild type
- signaling pathway
- lps induced
- mesenchymal stem cells
- dendritic cells
- endoplasmic reticulum stress
- cardiovascular disease
- immune response
- inflammatory response
- artificial intelligence
- dna binding
- cell death
- risk assessment
- big data
- long non coding rna
- hematopoietic stem cell