title: Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice.
abstract: OBJECTIVE
  Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE(-/-) mice.
  
  
  RESULTS
  Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG(-/-).apoE(-/-) mice) at 20, 40, and 60 weeks of age. Littermate OPG(+/+).apoE(-/-) mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG(-/-).apoE(-/-) mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG(-/-).apoE(-/-) mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells.
  
  
  CONCLUSIONS
  OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.
authors.affiliation: Department of Pathobiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.forename: Marta
authors.initials: M
authors.lastname: Scatena
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kirk
authors.forename: Marcello
authors.initials: M
authors.lastname: Rattazzi
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Varon
authors.forename: Michelle
authors.initials: M
authors.lastname: Averill
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Giachelli
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rosenfeld
mesh_terms: D000375:Aging; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D016122:Brachiocephalic Trunk / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival; D018450:Disease Progression; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D020780:Matrix Metalloproteinase 9; D002118:Calcium