title: Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes.
abstract: BACKGROUND
  Proteolytic degradation of Type I Collagen by proteases may play an important role in remodeling of atherosclerotic plaques, contributing to increased risk of plaque rupture.The aim of the current study was to investigate whether human macrophage foam cells degrade the extracellular matrix (ECM) of atherosclerotic plaques by cathepsin K mediated processes.
  
  
  METHODS
  We 1) cultured human macrophages on ECM and measured cathepsin K generated fragments of type I collagen (C-terminal fragments of Type I collagen (CTX-I) 2) investigated the presence of CTX-I in human coronary arteries and 3) finally investigated the clinical potential by measuring circulating CTX-I in women with and without radiographic evidence of aortic calcified atherosclerosis.
  
  
  RESULTS
  Immune-histochemistry of early and advanced lesions of coronary arteries demonstrated co-localization of Cathepsin-K and CTX-I in areas of intimal hyperplasia and in shoulder regions of advanced plaques. Treatment of human monocytes with M-CSF or M-CSF+LDL generated macrophages and foam cells producing CTX-I when cultured on type I collagen enriched matrix. Circulating levels of CTX-I were not significantly different in women with aortic calcifications compared to those without.
  
  
  CONCLUSIONS
  Human macrophage foam cells degrade the atherosclerotic plaques though cathepsin K mediated processes, resulting in increase in levels of CTX-I. Serum CTX-I was not elevated in women with aortic calcification, likely due to the contribution of CTX-I from osteoclastic bone resorption which involves Cathepsin-K. The human macrophage model system may be used to identify important pathway leading to excessive proteolytic plaque remodeling and plaque rupture.
authors.affiliation: Nordic Bioscience A/S, Herlev, DK-2730, Denmark. nb@nordicbioscience.com
authors.forename: Natasha
authors.initials: N
authors.lastname: Barascuk
authors.forename: Helene
authors.initials: H
authors.lastname: Skjøt-Arkil
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.forename: Lise
authors.initials: L
authors.lastname: Larsen
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
mesh_terms: D000328:Adult; D000368:Aged; D002114:Calcinosis; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D016893:Carotid Stenosis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D056657:Cathepsin K / Q000378:metabolism*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007120:Immunochemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D011859:Radiography
chemical_list: D024042:Collagen Type I; D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D016173:Macrophage Colony-Stimulating Factor; D056657:Cathepsin K
references.citation: Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1359-66
references.pmid: 15178558
references.citation: Eur J Clin Pharmacol. 2006 Oct;62(10):781-92
references.pmid: 16912870
references.citation: J Bone Miner Res. 2004 Sep;19(9):1432-40
references.pmid: 15312243
references.citation: Assay Drug Dev Technol. 2005 Oct;3(5):553-80
references.pmid: 16305312
references.citation: JAMA. 1994 Jan 26;271(4):289-94
references.pmid: 8295288
references.citation: Circulation. 2004 Mar 23;109(11):1408-14
references.pmid: 14993123
references.citation: J Bone Miner Metab. 2007;25(1):36-45
references.pmid: 17187192
references.citation: Biomarkers. 2009 May;14(3):181-202
references.pmid: 19399662
references.citation: Osteoporos Int. 2007 Jun;18(6):751-9
references.pmid: 17216130
references.citation: Circulation. 2007 Jan 30;115(4):450-8
references.pmid: 17190864
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):180-5
references.pmid: 15539621
references.citation: Eur J Clin Pharmacol. 2010 Jan;66(1):29-37
references.pmid: 19813008
references.citation: Annu Rev Physiol. 1997;59:63-88
references.pmid: 9074757
references.citation: J Bone Miner Res. 2007 Oct;22(10):1640-8
references.pmid: 17576165
references.citation: J Bone Miner Res. 2004 Jul;19(7):1144-53
references.pmid: 15176998
references.citation: Arteriosclerosis. 1986 Nov-Dec;6(6):585-93
references.pmid: 3535756
references.citation: Atherosclerosis. 2006 Nov;189(1):91-8
references.pmid: 16405893
references.citation: J Clin Endocrinol Metab. 1999 Jul;84(7):2363-8
references.pmid: 10404804
references.citation: J Biol Chem. 2007 Mar 16;282(11):7893-902
references.pmid: 17227755
references.citation: Am J Pathol. 2007 Mar;170(3):809-17
references.pmid: 17322367
references.citation: Semin Cell Dev Biol. 2008 Oct;19(5):424-33
references.pmid: 18768162
references.citation: FASEB J. 2007 Oct;21(12):3029-41
references.pmid: 17522380
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1119-27
references.pmid: 15802622
references.citation: Clin Chem. 1998 Nov;44(11):2281-9
references.pmid: 9799755
references.citation: Circulation. 2003 Apr 1;107(12):1626-31
references.pmid: 12668497
references.citation: Coll Relat Res. 1985 Sep;5(4):355-68
references.pmid: 3902343
references.citation: J Clin Invest. 2006 Jan;116(1):59-69
references.pmid: 16374516
references.citation: J Bone Miner Res. 2003 May;18(5):859-67
references.pmid: 12733725
references.citation: Ann N Y Acad Sci. 2006 Nov;1085:161-9
references.pmid: 17182932
references.citation: Circulation. 2004 Oct 12;110(15):2246-52
references.pmid: 15451790
references.citation: Arterioscler Thromb Vasc Biol. 2006 May;26(5):1120-5
references.pmid: 16556856
references.citation: Circulation. 2007 May 1;115(17):2292-8
references.pmid: 17420353
references.citation: Calcif Tissue Int. 2008 Dec;83(6):425-37
references.pmid: 18958510
references.citation: Osteoarthritis Cartilage. 2006 Aug;14(8):723-7
references.pmid: 16733093
references.citation: J Clin Invest. 1998 Aug 1;102(3):576-83
references.pmid: 9691094
references.citation: J Clin Invest. 2003 Mar;111(6):897-906
references.pmid: 12639996
references.citation: Circulation. 2006 Jan 3;113(1):98-107
references.pmid: 16365196
references.citation: Circulation. 2005 Apr 19;111(15):1883-90
references.pmid: 15837940
references.citation: J Biol Chem. 2003 Nov 7;278(45):44975-87
references.pmid: 12933809
references.citation: Diabetes Obes Metab. 2006 Jul;8(4):355-64
references.pmid: 16776742
references.citation: Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1430-6
references.pmid: 12750117
references.citation: Osteoarthritis Cartilage. 2006 Aug;14(8):738-48
references.pmid: 16563811
references.citation: Arch Intern Med. 2007 Dec 10;167(22):2437-42
references.pmid: 18071165
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13453-8
references.pmid: 9811821
references.citation: Circulation. 2002 Jun 11;105(23):2766-71
references.pmid: 12057992
references.citation: Atherosclerosis. 1997 Jul 25;132(2):245-50
references.pmid: 9242971
references.citation: J Pathol. 2001 Oct;195(3):375-82
references.pmid: 11673837