Osteoclastogenic Differentiation of Macrophages in the Development of Abdominal Aortic Aneurysms

Abstract

Objective-Arterial calcification is common and contributes to the pathogenesis of occlusive vascular disease. Similar to the dynamics of bone, it is a tightly controlled process that maintains a balance between osteogenesis and osteolysis. However, whether calcium homeostasis plays a role in the development of aneurysms has not been explored. We hypothesized that macrophages differentiate into osteoclasts in aneurysmal arteries and that protease byproducts contribute to aneurysm pathophysiology. Approach and Results-We performed histological and immunohistochemical analyses and showed that macrophages positive for several osteoclast markers, including tartrate acid phosphatase, occur in great numbers in the human aneurysmal aorta, but very few occur in the human stenotic aorta and none in the nondiseased human aorta. Moreover, in situ zymography showed elevated protease activity in these cells compared with undifferentiated macrophages. Tumor necrosis factor-α and calcium phosphate stimulated this osteoclastogenic differentiation process through nuclear factor-κB, mitogen-activated protein kinases, and intracellular calcium signaling but not the receptor activator of the nuclear factor-κB ligand. Inhibition of osteoclastogenic differentiation by bisphosphonate inhibits aneurysm development in a mouse model. Conclusions-These

Monocytes and macrophages in abdominal aortic aneurysm

“…Some investigators further revealed a differential mRNA and protein expression of MMP9 between M1 and M2 macrophages within the aneurysmal wall, suggesting that macrophages may differentially regulate ECM degradation depending on their phenotype and activation profile 47 . Another study identified macrophages positive for osteoclast markers in human aneurysmal aortas, and revealed higher protease activity in these cells compared to undifferentiated macrophages 102…”

Aortic Aneurysms

“…91 Their recent study has also provided evidence that calcification is present in human AAA, and pharmacological inhibition of osteoclastogenesis prevents the development of calcium phosphate-induced AAA in mice. 92 …”

Macrophage‐derived MMP‐9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits

“…This finding was initially unexpected and surprising, but it is possible that MMP‐9 may mediate vascular calcification through several possible molecular mechanisms . First, it has been reported that apoptotic macrophages in the lesions can release microcalcification‐generating matrix vesicles into the ECM, eventually resulting in calcification which is supported by our finding that macrophage‐rich lesions contained microcalcification. High expression of caspase‐3 in the lesions of Tg rabbits allowed us to speculate that increased cell death may be also involved in the process of vascular calcification.…”