title: Macrophage integrins modulate response to ultra-high molecular weight polyethylene particles and direct particle-induced osteolysis.
abstract: Aseptic loosening due to peri-prosthetic osteolysis is one of the primary causes for failure of artificial joint replacements. Implant-derived wear particles, often ultra-high molecular weight polyethylene (UHMWPE) microparticles, initiate an inflammatory cascade upon phagocytosis by macrophages, which leads to osteoclast recruitment and activation, ultimately resulting in osteolysis. Investigation into integrin receptors, involved in cellular interactions with biomaterial-adsorbed adhesive proteins, is of interest to understand and modulate inflammatory processes. In this work, we investigate the role of macrophage integrins Mac-1 and RGD-binding integrins in response to UHMWPE wear particles. Using integrin knockout mice as well as integrin blocking techniques, reduction in macrophage phagocytosis and inflammatory cytokine secretion is demonstrated when these receptors are either absent or blocked. Along this line, various opsonizing proteins are shown to differentially modulate microparticle uptake and macrophage secretion of inflammatory cytokines. Furthermore, using a calvarial osteolysis model it is demonstrated that both Mac-1 integrin and RGD-binding integrins modulate the particle induced osteolysis response to UHMWPE microparticles, with a 40% decrease in the area of osteolysis by the absence or blocking of these integrins, in vivo. Altogether, these findings indicate Mac-1 and RGD-binding integrins are involved in macrophage-directed inflammatory responses to UHMWPE and may serve as therapeutic targets to mitigate wear particle induced peri-prosthetic osteolysis for improved performance of implanted joints.
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Food Science, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Toral D
authors.initials: TD
authors.lastname: Zaveri
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Dolgova
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Biomedical Engineering, University of California, Davis, Davis, CA 95618, USA.
authors.forename: Jamal S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Kiri
authors.initials: K
authors.lastname: Hamaker
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clare-Salzler
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA. Electronic address: bgk@ufl.edu.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Keselowsky
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000633:toxicity*; D002460:Cell Line; D005260:Female; D016023:Integrins / Q000276:immunology*; D007595:Joint Prosthesis / Q000009:adverse effects*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053758:Nanoparticles / Q000633:toxicity; D010014:Osteolysis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D010316:Particle Size; D011095:Polyethylenes / Q000633:toxicity*; D011475:Prosthesis Failure
chemical_list: D001672:Biocompatible Materials; D016023:Integrins; D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene
keywords: Cell adhesion; Implant; Inflammation; Integrin; Macrophage; Osteolysis