Tumor necrosis factor-α and receptor activator of nuclear factor-κB ligand augment human macrophage foam-cell destruction of extracellular matrix through protease-mediated processes

Helene Skjøt-Arkil, Natasha Barascuk, Lise Larsen, Morten Dziegiel, Kim Henriksen, Morten A Karsdal

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

By secreting proteases such as cathepsins and matrix metalloproteinases (MMPs), macrophage foam cells may be a major cause of ruptured atherosclerotic plaques. The aims of the present study were to investigate in vitro role of human macrophage foam cells in degrading type I collagen, a major component of extracellular matrix (ECM) in plaques, and to establish whether the pro-inflammatory molecules, tumor necrosis factor (TNF)-alpha, and receptor activator of nuclear factor-κB ligand (RANK-L) increase this degradation. CD14+ monocytes isolated from peripheral blood were differentiated into macrophage foam cells and cultured on a type I collagen matrix in the presence of TNF-alpha and RANK-L. Matrix degradation was measured by the cathepsin K-generated C-terminal cross-linked telopeptide of type I collagen (CTX-I) and the MMP-generated carboxyterminal telopeptide of type I collagen (ICTP) in supernatants showing that macrophage foam cells secrete MMPs and cathepsin K, resulting in release of ICTP and CTX-I. Stimulation with TNF-alpha increased CTX-I and ICTP dose dependently, with ICTP levels increasing by 59% and CTX-I levels increasing by 43%. RANK-L enhanced the release of CTX-I and ICTP by 56% and 72%, respectively. This is, to our knowledge, the first data describing a simple in vitro system in which macrophage foam cells degradation of matrix proteins can be monitored. This degradation can be enhanced by cytokines since TNF-alpha and RANK-L significantly increased the matrix degradation. This in vitro system in part is a model system for the macrophage-mediated proteolytic degradation of the ECM, which is found in many diseases with an inflammatory component.

OriginalsprogEngelsk
TidsskriftASSAY and Drug Development Technologies
Vol/bind10
Udgave nummer1
Sider (fra-til)69-77
ISSN1540-658X
DOI
StatusUdgivet - 2012

Fingeraftryk

Foam Cells
Tumor Necrosis Factor Receptors
Peptide Hydrolases
Macrophages
Collagen Type I
Ligands
Tumor Necrosis Factor-alpha
Matrix Metalloproteinases
Cathepsin K
Cathepsins
Atherosclerotic Plaques
Proteolysis
In Vitro Techniques

Citer dette

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title = "Tumor necrosis factor-α and receptor activator of nuclear factor-κB ligand augment human macrophage foam-cell destruction of extracellular matrix through protease-mediated processes",
abstract = "By secreting proteases such as cathepsins and matrix metalloproteinases (MMPs), macrophage foam cells may be a major cause of ruptured atherosclerotic plaques. The aims of the present study were to investigate in vitro role of human macrophage foam cells in degrading type I collagen, a major component of extracellular matrix (ECM) in plaques, and to establish whether the pro-inflammatory molecules, tumor necrosis factor (TNF)-alpha, and receptor activator of nuclear factor-κB ligand (RANK-L) increase this degradation. CD14+ monocytes isolated from peripheral blood were differentiated into macrophage foam cells and cultured on a type I collagen matrix in the presence of TNF-alpha and RANK-L. Matrix degradation was measured by the cathepsin K-generated C-terminal cross-linked telopeptide of type I collagen (CTX-I) and the MMP-generated carboxyterminal telopeptide of type I collagen (ICTP) in supernatants showing that macrophage foam cells secrete MMPs and cathepsin K, resulting in release of ICTP and CTX-I. Stimulation with TNF-alpha increased CTX-I and ICTP dose dependently, with ICTP levels increasing by 59{\%} and CTX-I levels increasing by 43{\%}. RANK-L enhanced the release of CTX-I and ICTP by 56{\%} and 72{\%}, respectively. This is, to our knowledge, the first data describing a simple in vitro system in which macrophage foam cells degradation of matrix proteins can be monitored. This degradation can be enhanced by cytokines since TNF-alpha and RANK-L significantly increased the matrix degradation. This in vitro system in part is a model system for the macrophage-mediated proteolytic degradation of the ECM, which is found in many diseases with an inflammatory component.",
keywords = "Atherosclerosis, Biomarkers, Cathepsin K, Cells, Cultured, Collagen Type I, Extracellular Matrix, Foam Cells, Humans, Inflammation Mediators, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Peptides, RANK Ligand, Tumor Necrosis Factor-alpha, Up-Regulation",
author = "Helene Skj{\o}t-Arkil and Natasha Barascuk and Lise Larsen and Morten Dziegiel and Kim Henriksen and Karsdal, {Morten A}",
year = "2012",
doi = "10.1089/adt.2010.0366",
language = "English",
volume = "10",
pages = "69--77",
journal = "ASSAY and Drug Development Technologies",
issn = "1540-658X",
publisher = "Mary Ann Liebert Incorporated",
number = "1",

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TY - JOUR

T1 - Tumor necrosis factor-α and receptor activator of nuclear factor-κB ligand augment human macrophage foam-cell destruction of extracellular matrix through protease-mediated processes

AU - Skjøt-Arkil, Helene

AU - Barascuk, Natasha

AU - Larsen, Lise

AU - Dziegiel, Morten

AU - Henriksen, Kim

AU - Karsdal, Morten A

PY - 2012

Y1 - 2012

N2 - By secreting proteases such as cathepsins and matrix metalloproteinases (MMPs), macrophage foam cells may be a major cause of ruptured atherosclerotic plaques. The aims of the present study were to investigate in vitro role of human macrophage foam cells in degrading type I collagen, a major component of extracellular matrix (ECM) in plaques, and to establish whether the pro-inflammatory molecules, tumor necrosis factor (TNF)-alpha, and receptor activator of nuclear factor-κB ligand (RANK-L) increase this degradation. CD14+ monocytes isolated from peripheral blood were differentiated into macrophage foam cells and cultured on a type I collagen matrix in the presence of TNF-alpha and RANK-L. Matrix degradation was measured by the cathepsin K-generated C-terminal cross-linked telopeptide of type I collagen (CTX-I) and the MMP-generated carboxyterminal telopeptide of type I collagen (ICTP) in supernatants showing that macrophage foam cells secrete MMPs and cathepsin K, resulting in release of ICTP and CTX-I. Stimulation with TNF-alpha increased CTX-I and ICTP dose dependently, with ICTP levels increasing by 59% and CTX-I levels increasing by 43%. RANK-L enhanced the release of CTX-I and ICTP by 56% and 72%, respectively. This is, to our knowledge, the first data describing a simple in vitro system in which macrophage foam cells degradation of matrix proteins can be monitored. This degradation can be enhanced by cytokines since TNF-alpha and RANK-L significantly increased the matrix degradation. This in vitro system in part is a model system for the macrophage-mediated proteolytic degradation of the ECM, which is found in many diseases with an inflammatory component.

AB - By secreting proteases such as cathepsins and matrix metalloproteinases (MMPs), macrophage foam cells may be a major cause of ruptured atherosclerotic plaques. The aims of the present study were to investigate in vitro role of human macrophage foam cells in degrading type I collagen, a major component of extracellular matrix (ECM) in plaques, and to establish whether the pro-inflammatory molecules, tumor necrosis factor (TNF)-alpha, and receptor activator of nuclear factor-κB ligand (RANK-L) increase this degradation. CD14+ monocytes isolated from peripheral blood were differentiated into macrophage foam cells and cultured on a type I collagen matrix in the presence of TNF-alpha and RANK-L. Matrix degradation was measured by the cathepsin K-generated C-terminal cross-linked telopeptide of type I collagen (CTX-I) and the MMP-generated carboxyterminal telopeptide of type I collagen (ICTP) in supernatants showing that macrophage foam cells secrete MMPs and cathepsin K, resulting in release of ICTP and CTX-I. Stimulation with TNF-alpha increased CTX-I and ICTP dose dependently, with ICTP levels increasing by 59% and CTX-I levels increasing by 43%. RANK-L enhanced the release of CTX-I and ICTP by 56% and 72%, respectively. This is, to our knowledge, the first data describing a simple in vitro system in which macrophage foam cells degradation of matrix proteins can be monitored. This degradation can be enhanced by cytokines since TNF-alpha and RANK-L significantly increased the matrix degradation. This in vitro system in part is a model system for the macrophage-mediated proteolytic degradation of the ECM, which is found in many diseases with an inflammatory component.

KW - Atherosclerosis

KW - Biomarkers

KW - Cathepsin K

KW - Cells, Cultured

KW - Collagen Type I

KW - Extracellular Matrix

KW - Foam Cells

KW - Humans

KW - Inflammation Mediators

KW - Matrix Metalloproteinase 2

KW - Matrix Metalloproteinase 9

KW - Peptides

KW - RANK Ligand

KW - Tumor Necrosis Factor-alpha

KW - Up-Regulation

U2 - 10.1089/adt.2010.0366

DO - 10.1089/adt.2010.0366

M3 - Journal article

VL - 10

SP - 69

EP - 77

JO - ASSAY and Drug Development Technologies

JF - ASSAY and Drug Development Technologies

SN - 1540-658X

IS - 1

ER -