Abstract 9593: Osteoclastogenesis as a Novel Therapeutic Target for Abdominal Aortic Aneurysm
Arterial calcification has been proven to be the result of highly organized processes as seen in bone which relies upon a delicate balance between osteoblasts and osteoclasts. Osteoclast-like cells (OLCs) are derived from the monocyte/macrophage lineage and share features of osteoclasts, including the ability to dissolve extracellular matrix. Although osteoclastogenesis has been reported to occur in calcified arteries, its potential role in the development of abdominal aortic aneurysm (AAA) has yet to be explored. Here, we examined the role of OLCs in the development of AAA. Firstly, we obtained aortic tissues from patients undergoing surgical repair for AAA (N = 5) and aortic occlusive disease (N = 5). Alizarin-Red staining showed calcification in both aneurysmal and occlusive aorta. In contrast, OLCs, recognized as multi-nucleated cells positive for enzymatic TRAP staining, were identified only in aneurysmal aorta (100%, 5 of 5). A time course experiment in mouse calcium chloride-induced AAA (CaCl2 AAA) showed calcium deposition and monocyte/macrophage accumulation starting at 48 hours post-surgery followed by OLC formation, peaking 7 days after CaCl2 injury. Secondly, we administered bisphosphonate (Zoledronic acid, 0.1 mg/kg, once), an inhibitor of osteoclasts, or normal saline as a control, intravenously to mouse after CaCl2 injury (N = 3). Bisphosphonate-treated mice showed a significant reduction in arterial dilation after 7 and 42 days with a mean fold change of 1.08 ± 0.09 vs. 1.62 ± 0.05 (P < 0.01) and 1.24 ± 0.12 vs. 2.26 ± 0.06 (P<0.01), respectively. We also studied the effect of bisphosphonate on “developed aneurysm” by delaying the injection until one week after the injury (N = 5). Bisphosphonate significantly delayed a further expansion of the aneurysm with a percent increase from 7 to 42 days of 11.5% vs. 63.6% (P < 0.01). Finally, mice treated with a neutralizing antibody to RANKL (1mg/kg), a key factor for osteoclast differentiation, showed a significant inhibition at 7 days (N = 3) (1.19 ± 0.06 vs. 1.62 ± 0.05, P < 0.01). In conclusion, we have demonstrated the existence of OLCs in AAA and the inhibitory effect of bisphosphonate and anti-RANKL antibody on aneurysm. These results suggest that OLCs could be a novel therapeutic target for AAA.
- © 2011 by American Heart Association, Inc.