Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes.
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.
Barascuk
Natasha
N
Nordic Bioscience A/S, Herlev, DK-2730, Denmark. nb@nordicbioscience.com
Skjøt-Arkil
Helene
H
Register
Thomas C
TC
Larsen
Lise
L
Byrjalsen
Inger
I
Christiansen
Claus
C
Karsdal
Morten A
MA
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
D024042:Collagen Type I; D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D016173:Macrophage Colony-Stimulating Factor; D056657:Cathepsin K
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