Persistence of Vascular Calcification: A Failure of Cell-Mediated Resorption

BACKGROUND: Medial arterial calcification is a common lesion associated with aging, chronic kidney disease, and diabetes that can lead to poor outcomes. Because the calcification is extensive when first apparent clinically or even radiologically, optimal therapy should target reversal in addition to prevention. However, studies to date suggest that medial calcification is irreversible under physiological conditions. This lack of reversal was investigated further by implanting calcified human arteries or hydroxyapatite subcutaneously into mice, or culturing them with murine osteoclasts in vitro. METHODS: Calcified human tibial arteries, obtained from amputations and previously frozen, were implanted subcutaneously in the dorsum of mice. Mineral content was measured by microcomputed tomography before and after implantation and compared with the calcium content of implanted pure hydroxyapatite or murine bone particles, along with histology. Calcified arteries were also incubated in vitro with osteoclasts generated by treating murine macrophages with receptor activator of NF-κB (nuclear factor kappa B). RESULTS: There was no decrease in mineral content of implanted arteries over 6 weeks and only minimal loss of calcium in devitalized bone particles, compared with almost complete resorption of hydroxyapatite. No resorption of hydroxyapatite occurred when implanted within a cell-impermeable diffusion chamber. Multinucleated giant cells, negative for osteoclast markers, were numerous among implanted hydroxyapatite, but rare in implanted arteries and bone. There was no histological evidence of resorption in calcified arteries incubated with osteoclasts. CONCLUSIONS: Hydroxyapatite is readily reabsorbed in vivo by a cell-mediated process not involving osteoclasts. The lack of resorption of medial arterial calcifications, even in the presence of osteoclasts, indicates that calcifications have properties that prevent cell-mediated resorption. Further studies are needed to identify these properties and develop strategies to overcome this.