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

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.