title: Toll-like receptors in the interface membrane around loosening total hip replacement implants.
abstract: Toll-like receptors (TLRs) have been known to act as sensors of innate immunity and respond to ligands of microbial and endogenous components. Tissues and cells typical for interface membrane of foreign body reaction were analyzed to evaluate potential role of TLRs in the pathogenesis of the so called "aseptic loosening of total hip replacement." Fourteen cases of interface membrane around aseptic loose total hip replacement implants were stained by single and double immunohistochemical methods to examine cellular localization of toll-like receptor (TLR)-4 and TLR-9. Osteoarthritic synovium was used as control tissues. Cultured macrophages were used to study TLR-4 and TLR-9 mRNA levels by quantitative reverse transcriptase-polymerase chain reaction. The effect of titanium particle stimulation on macrophages was also examined in the culture. Extensive immunolocalization of TLR-4 and TLR-9 positive cells was observed in the synovial membrane-like interface membrane of foreign body granulomas compared with control synovial membranes. TLR and CD68 double staining demonstrated that the TLR positive cells in aseptic loosening were mostly monocyte/macrophages and foreign body giant cells. TLR-4 and TLR-9 mRNA expression was also found in macrophage-colony stimulating factor treated rat macrophages, but this expression decreased (p < 0.05 or less) upon stimulation with titanium particles although matrix metalloproteinase (MMP)-9 mRNA levels used as macrophage activation marker were increased (p = 0.01). The interface membrane around loosening total hip replacement implants is apparently well equipped with TLRs and, thus, probably very sensitive to various structural components of microbes and to endogenous TLR ligands. This seems to be due to recruitment of monocyte/macrophages as particles per se seemed to down-regulate some of the key TLRs. This suppression after particle phagocytosis might prevent excessive and harmful host responses, and injury to innocent bystander cells/tissues.
authors.affiliation: Department of Orthopaedic Surgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan. mtakagi@med.id.yamagata-u.ac.jp
authors.forename: Michiaki
authors.initials: M
authors.lastname: Takagi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Yuya
authors.initials: Y
authors.lastname: Takakubo
authors.forename: Liisa
authors.initials: L
authors.lastname: Konttinen
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Tiainen
authors.forename: Reijo
authors.initials: R
authors.lastname: Lappalainen
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Jari
authors.initials: J
authors.lastname: Salo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D019644:Arthroplasty, Replacement, Hip; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D008566:Membranes; D008875:Middle Aged; D011475:Prosthesis Failure; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000187:drug effects; D014025:Titanium / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014025:Titanium; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C495345:TLR4 protein, human; C495371:TLR9 protein, human