title: Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials.
abstract: Matrix metalloproteinases (MMPs) can degrade structural components within the extracellular matrix and at the cellular surface producing changes in cellular behavior (i.e., adhesion and migration) and subsequent pathological responses (i.e., the foreign body reaction and wound healing). We continue to study the foreign body reaction that occurs following biomaterial implantation by investigating secretory responses of biomaterial-adherent macrophages and foreign body giant cells (FBGCs) as directed by material surface chemistry and further this research by determining whether secreted MMPs play a role in macrophage adhesion and fusion. We have identified numerous MMPs and their tissue inhibitors (TIMPs) in in vitro cell-culture supernatants using antibody arrays and quantified select MMP/TIMPs with ELISAs. MMP-9 concentrations were significantly greater than both TIMP-1 and TIMP-2 on all materials. The ratios of MMP-9/TIMP-1 and MMP-9/TIMP-2 increased with time because of an increase in MMP-9 concentrations over time, while the TIMP concentrations remained constant. Total MMP-9 concentrations in the supernatants were comparable on all materials at each timepoint, while TIMP-1 and TIMP-2 concentrations tended to be greater on hydrophilic/anionic surfaces. Analysis of the MMP/TIMP quantities produced per cell revealed that the hydrophilic/neutral surfaces, which inhibited macrophage adhesion, activated the adherent macrophages/FBGCs to produce a greater quantity of MMP-9, TIMP-1, and TIMP-2 per cell. Pharmacological inhibition of MMP-1,-8,-13, and -18 reduced macrophage fusion without affecting adhesion, while inhibitors of MMP-2,-3,-9, and -12 did not affect adhesion or fusion. These findings demonstrate that material surface chemistry does modulate macrophage/FBGC-derived MMP/TIMP secretion and implicates MMP involvement in macrophage fusion.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Jones
authors.forename: Amy K
authors.initials: AK
authors.lastname: McNally
authors.forename: David T
authors.initials: DT
authors.lastname: Chang
authors.forename: L Abigail
authors.initials: LA
authors.lastname: Qin
authors.forename: Howard
authors.initials: H
authors.lastname: Meyerson
authors.forename: Erica
authors.initials: E
authors.lastname: Colton
authors.forename: I L Keun
authors.initials: IL
authors.lastname: Kwon
authors.forename: Takehisa
authors.initials: T
authors.lastname: Matsuda
authors.forename: James M
authors.initials: JM
authors.lastname: Anderson
mesh_terms: D000906:Antibodies; D001672:Biocompatible Materials / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005549:Foreign-Body Reaction / Q000201:enzymology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000276:immunology / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D040081:Protein Array Analysis; D013379:Substrate Specificity; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D001672:Biocompatible Materials; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D019714:Tissue Inhibitor of Metalloproteinases; C047981:arginyl-glycyl-aspartic acid; D020782:Matrix Metalloproteinases