Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis

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.

Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis

“…Since somatic mutations of menin in other tissues have been described ( 51,52 ) and somatic mutations of other genes have been implicated in osteoporosis, (53 ) it is important to know how menin deletion might affect bone turnover depending on the stage of the osteoblastic cell that is impacted. Thus, in contrast to our present results, we previously deleted menin from mature osteoblasts and osteocytes using the same floxed menin allele but using Osteocalcin‐Cre as the cre driver; we also overexpressed menin in the mature osteoblast.…”

Postnatal conservation of human blood- and marrow-specific CD34+ hematopoietic phenotypes

“…Notably, transplants of cells obtained from older donors have been associated with suboptimal outcomes [36][37][38][39] . In addition, advanced age is now also a well-established risk for an increasing number of sequelae associated with clonal hematopoiesis of indeterminate potential [40][41][42][43][44][45] . Thus, obtaining additional and precise insights into the effects on normal human aging on the cellular changes that regulate primitive hematopoietic cell behaviour remain important goals best served by combined measurements of the functional properties of individually characterized phenotypes.…”

Bone marrow runs the (bone) show

“…The incidence of CHIP increases with age, and affected individuals are at a higher risk than nonaffected ones of developing hematological malignancies and, most curiously, coronary heart disease ( Steensma et al, 2015 ). What Kim et. al.…”

“…Nowadays, it is universally accepted that cytokines made by various cellular components of the bone marrow can and do affect bone (re)modeling ( Fischer and Haffner-Luntzer, 2021 ). In this issue of JEM , Kim et. al.…”