title: Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles.
abstract: The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-α in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-α among MyD88 knockout (MyD88(-/-)), TRIF knockout (TRIF(-/-)), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-α. Gene expression data indicated that this latter increase in TNF-α was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88(-/-) mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.
authors: Department of Orthopaedic Surgery, Stanford University Medical Center, 450 Broadway Street, M/C 6342, Redwood City, CA 94063, USA.
authors: Jeremy I
authors: JI
authors: Pearl
authors: Ting
authors: T
authors: Ma
authors: Afraaz R
authors: AR
authors: Irani
authors: Zhinong
authors: Z
authors: Huang
authors: William H
authors: WH
authors: Robinson
authors: Robert L
authors: RL
authors: Smith
authors: Stuart B
authors: SB
authors: Goodman
references: Genes Dev. 1999 Apr 15;13(8):1015-24
references: 10215628
references: J Exp Med. 2004 Sep 6;200(5):601-11
references: 15353553
references: J Exp Med. 2005 Mar 21;201(6):915-23
references: 15767370
references: J Bone Miner Res. 2001 Nov;16(11):2082-91
references: 11697805
references: Nat Protoc. 2008;3(6):1101-8
references: 18546601
references: J Clin Invest. 2007 Aug;117(8):2197-204
references: 17657310
references: Biomaterials. 2005 Apr;26(11):1271-86
references: 15475057
references: EMBO J. 2000 Aug 1;19(15):4154-63
references: 10921895
references: Am J Pathol. 1999 Jan;154(1):203-10
references: 9916934
references: J Immunol. 2009 Jun 1;182(11):6889-95
references: 19454685
references: J Exp Med. 2005 Sep 5;202(5):589-95
references: 16147974
references: Immunol Ser. 1992;56:3-34
references: 1550865
references: Nat Rev Immunol. 2002 Oct;2(10):725-34
references: 12360211
references: Clin Orthop Relat Res. 2001 Dec;(393):71-7
references: 11764373
references: Genes Dev. 1998 Sep 15;12(18):2821-30
references: 9744859
references: Annu Rev Immunol. 2003;21:335-76
references: 12524386
references: Nature. 2004 Jul 8;430(6996):257-63
references: 15241424
references: Nat Immunol. 2001 Aug;2(8):675-80
references: 11477402
references: Diabetes Care. 1998 Aug;21(8):1310-6
references: 9702439
references: J Immunol. 2002 Nov 15;169(10):5874-80
references: 12421970
references: Diabetes. 2001 Dec;50(12):2792-808
references: 11723063
references: J Biomed Mater Res. 2000 Mar 15;49(4):469-78
references: 10602080
references: Nat Med. 1997 Nov;3(11):1285-9
references: 9359707
references: J Biol Chem. 2005 Apr 22;280(16):15809-14
references: 15755740
references: J Biol Chem. 2003 May 9;278(19):16732-40
references: 12611893
references: Circulation. 1997 Oct 7;96(7):2262-71
references: 9337199
references: J Comp Pathol. 1998 Jul;119(1):89-93
references: 9717131
references: Science. 2005 Sep 16;309(5742):1854-7
references: 16166516
references: J Leukoc Biol. 2004 Jul;76(1):42-7
references: 15075353
references: Clin Orthop Relat Res. 2001 Dec;(393):66-70
references: 11764372
references: Bone. 1998 Jul;23(1):59-66
references: 9662131
references: Nature. 1997 Jul 24;388(6640):394-7
references: 9237759
references: J Biol Chem. 2002 Jun 7;277(23):20431-7
references: 11923281
references: J Immunol. 2000 Apr 15;164(8):4301-6
references: 10754329