title: Toll-like receptors-2 and 4 are overexpressed in an experimental model of particle-induced osteolysis.
abstract: Aseptic loosening secondary to particle-associated periprosthetic osteolysis remains a major cause of failure of total joint replacements (TJR) in the mid- and long term. As sentinels of the innate immune system, macrophages are central to the recognition and initiation of the inflammatory cascade, which results in the activation of bone resorbing osteoclasts. Toll-like receptors (TLRs) are involved in the recognition of pathogen-associated molecular patterns and danger-associated molecular patterns. Experimentally, polymethylmethacrylate and polyethylene (PE) particles have been shown to activate macrophages via the TLR pathway. The specific TLRs involved in PE particle-induced osteolysis remain largely unknown. We hypothesized that TLR-2, -4, and -9 mediated responses play a critical role in the development of PE wear particle-induced osteolysis in the murine calvarium model. To test this hypothesis, we first demonstrated that PE particles caused observable osteolysis, visible by microCT and bone histomorphometry when the particles were applied to the calvarium of C57BL/6 mice. The number of TRAP positive osteoclasts was significantly greater in the PE-treated group when compared to the control group without particles. Finally, using immunohistochemistry, TLR-2 and TLR-4 were highly expressed in PE particle-induced osteolytic lesions, whereas TLR-9 was downregulated. TLR-2 and -4 may represent novel therapeutic targets for prevention of wear particle-induced osteolysis and accompanying TJR failure.
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California.
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Valladares
authors.forename: Christophe
authors.initials: C
authors.lastname: Nich
authors.forename: Stefan
authors.initials: S
authors.lastname: Zwingenberger
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Swank
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gibon
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Rao
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
mesh_terms: D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010014:Osteolysis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D020959:Polyethylene / Q000009:adverse effects*; D011475:Prosthesis Failure / Q000009:adverse effects; D012886:Skull / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000032:analysis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000032:analysis / Q000276:immunology
chemical_list: D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D020959:Polyethylene
keywords: arthroplasty; immune response; murine calvarium; osteolysis; polyethylene; toll-like receptor; ultra high molecular weight polyethylene; wear debris