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.
authors: Nordic Bioscience A/S, Herlev, Denmark. hbe@nordicbioscience.com
authors: Helene
authors: H
authors: Skjøt-Arkil
authors: Natasha
authors: N
authors: Barascuk
authors: Lise
authors: L
authors: Larsen
authors: Morten
authors: M
authors: Dziegiel
authors: Kim
authors: K
authors: Henriksen
authors: Morten A
authors: MA
authors: Karsdal
mesh_terms: D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D056657:Cathepsin K / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D010455:Peptides / Q000502:physiology; D053245:RANK Ligand / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D018836:Inflammation Mediators; D010455:Peptides; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; C052929:collagen type I trimeric cross-linked peptide; C534130:CTSK protein, human; D056657:Cathepsin K; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9