Expanding clones, expanding aneurysms through macrophage-to-osteoclast differentiation
Jessica A. Regan, Svati H. Shah
Jessica A. Regan, Svati H. Shah
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Commentary

Expanding clones, expanding aneurysms through macrophage-to-osteoclast differentiation

Abstract

Abdominal aortic aneurysms (AAAs) are an age-related cause of sudden cardiac death and cardiovascular disease (CVD) morbidity with limited nonsurgical treatment options. In this issue of the JCI, Yonekawa et al. addressed the pathobiologic mechanisms of clonal hematopoiesis (CH), the age-related acquisition of expanded somatic clones in blood cells, as a potential driver of AAA. CH prevalence was high in patients being treated for AAA, and faster AAA expansion occurred over a period of one year in CH carriers. In an angiotensin II–induced model of AAA, mice carrying ten-eleven translocation 2 (Tet2) mutations (Tet2-CH) displayed accelerated AAA development and macrophage reprograming to an osteoclast-like state. Inhibition of this differentiation, targeting RANK/RANKL with FDA-approved therapies like alendronate and denosumab, suppressed aneurysmal growth. These findings suggest that macrophage-to-osteoclast differentiation may underlie the risk and progression of AAA associated with age-related CH, a mechanism that is modifiable through existing therapeutics.

Authors

Jessica A. Regan, Svati H. Shah

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Figure 1

Expanding CH clones promote aneurysm growth via macrophage-to-osteoclast–like differentiation.

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Expanding CH clones promote aneurysm growth via macrophage-to-osteoclast...
(A) Yonekawa et al. (7) identified a mechanism of TET2-CH–driven AAA via RANK/RANKL-dependent macrophage-to-osteoclast–like immune cell differentiation. Aortic macrophages isolated from Tet2-CH mice were characterized by upregulation of TRAP and MMP9 expression, and both the TRAP+ differentiation and the aneurysm phenotype in Tet2-CH mice could be inhibited by genetic or pharmacologic targeting of RANK/RANKL. (B) Distinct mechanisms of TET2-CH–driven immune cell differentiation have been described for AAA by Yonekawa et al. (7) versus aortic valve stenosis by Abplanalp et al. (12). While Yonekawa et al. (7) found osteoclast-like differentiation to cause extracellular matrix degradation in AAA, Abplanalp et al. (12) described paracrine effects of OSM and S100A9 to stimulate mesenchymal cell–to-osteoblast transitions contributing to matrix mineralization and calcifications.