Tumor Necrosis Factor-Alpha and Receptor Activator of Nuclear Factor-κB Ligand Augment Human Macrophage Foam-Cell Destruction of Extracellular Matrix Through Protease-Mediated Processes
| Autor: | Morten A. Karsdal, Kim Henriksen, Natasha Barascuk, Morten Dziegiel, Lise Larsen, Helene Skjøt-Arkil |
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| Rok vydání: | 2012 |
| Předmět: |
Cathepsin K
Matrix metallopeptidase 12 Matrix metalloproteinase Collagen Type I Extracellular matrix Drug Discovery Humans Cells Cultured Foam cell Cathepsin Tumor Necrosis Factor-alpha Chemistry RANK Ligand Atherosclerosis Extracellular Matrix Up-Regulation Cell biology Matrix Metalloproteinase 9 Biochemistry Matrix Metalloproteinase 2 Molecular Medicine Inflammation Mediators Peptides Biomarkers Type I collagen Foam Cells |
| Zdroj: | Skjøt-Arkil, H, Barascuk, N, Larsen, L, Dziegiel, M, Henriksen, K & Karsdal, M A 2012, ' 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 ', ASSAY and Drug Development Technologies, vol. 10, no. 1, pp. 69-77 . https://doi.org/10.1089/adt.2010.0366 |
| ISSN: | 1557-8127 1540-658X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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