title: Osteoclastogenic Differentiation of Macrophages in the Development of Abdominal Aortic Aneurysms.
abstract: 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.
  
  
  
  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.
  
  
  
  These results suggest that differentiation of macrophages into osteoclasts contributes to the pathophysiology of aneurysmal disease.
authors.affiliation: From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Takei
authors.affiliation: From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: K Craig
authors.initials: KC
authors.lastname: Kent
authors.affiliation: From the Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison. yamano@surgery.wisc.edu.
authors.forename: Dai
authors.initials: D
authors.lastname: Yamanouchi
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002122:Calcium Chloride; D002130:Calcium Phosphates / Q000494:pharmacology; D020013:Calcium Signaling; D054338:Cell Transdifferentiation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D000067996:RAW 264.7 Cells; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D061205:Vascular Calcification / Q000378:metabolism* / Q000473:pathology
chemical_list: D002130:Calcium Phosphates; D004164:Diphosphonates; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C020243:calcium phosphate; D000071681:Tartrate-Resistant Acid Phosphatase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D002122:Calcium Chloride
keywords: aneurysm; cardiovascular diseases; metalloproteinases; osteogenesis; osteolysis