title: Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties.
abstract: Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase- or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors that were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP- and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the losses of dynamic compression and shear moduli were delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wilson
authors.forename: Ashley W
authors.initials: AW
authors.lastname: Palmer
authors.forename: Fengrong
authors.initials: F
authors.lastname: Zuo
authors.forename: Elsie
authors.initials: E
authors.lastname: Eugui
authors.forename: Stacy
authors.initials: S
authors.lastname: Wilson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mackenzie
authors.forename: John D
authors.initials: JD
authors.lastname: Sandy
authors.forename: Marc E
authors.initials: ME
authors.lastname: Levenston
mesh_terms: D053674:Aggrecans / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000166:cytology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000378:metabolism*; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D053674:Aggrecans; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D010450:Endopeptidases; D045726:Metalloproteases; C083641:aggrecanase