Wear particle-induced inflammation is a major factor contributing to aseptic loosening in peri-prosthetic tissue. The effects of cannabinoid receptor 2 (CB2) on wear particle-induced inflammation remain unclear. Reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assay were used to assess the effects of a CB2-selective antagonist, AM630, on regulation of the inflammatory reaction and production of pro-inflammatory cytokines in response to in vitro and in vivo stimulation with titanium particles. In vitro studies, in a model for pre-osteoclast-like cells, demonstrated that AM630 inactivation of CB2 profoundly inhibited interleukin (IL)-1β and tumour necrosis factor (TNF)-α production by RAW264.7 cells stimulated with titanium particles. In vivo findings in a murine air-pouch model of titanium-induced inflammatory osteolysis indicated that AM630 reduced titanium-induced tissue inflammation, seen as a reduction in pouch membrane thickness, inflammatory infiltration and levels of the pro-inflammatory cytokines IL-1β and TNF-α. Thus, inactivation of CB2 by AM630 inhibited the titanium particle-induced inflammatory reaction by reducing pro-inflammatory cytokines in vitro and in vivo.
GoodmanSB: Wear particles, periprosthetic osteolysis and the immune system. Biomaterials2007; 28: 5044–5048.
2.
KanajiACaicedoMSVirdiAS: Co–Cr–Mo alloy particles induce tumor necrosis factor alpha production in MLO-Y4 osteocytes: A role for osteocytes in particle-induced inflammation. Bone2009; 45: 528–533.
3.
PurduePEKoulouvarisPPotterHG: The cellular and molecular biology of periprosthetic osteolysis. Clin Orthop Relat Res2007; 454: 251–261.
4.
ShanbhagASJacobsJJBlackJ: Cellular mediators secreted by interfacial membranes obtained at revision total hip arthroplasty. J Arthroplasty199510: 498–506.
ChildsLMGoaterJJO'KeefeRJ: Effect of anti-tumor necrosis factor-α gene therapy on wear debris-induced osteolysis. J Bone Joint Surg Am2001; 83-A: 1789–1797.
7.
GordonAKiss-TothEStockleyI: Polymorphisms in the interleukin-1 receptor antagonist and interleukin-6 genes affect risk of osteolysis in patients with total hip arthroplasty. Arthritis Rheum2008; 58: 3157–3165.
8.
TakiNTatroJMLoweR: Comparison of the roles of IL-1, IL-6, and TNFα in cell culture and murine models of aseptic loosening. Bone2007; 40: 1276–1283.
9.
YangSYWuBMaytonL: Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear particles-induced osteolysis. Gene Ther2004; 11: 483–491.
10.
MackieK: Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol2006; 46: 101–122.
11.
PereiraJPAnJXuY: Cannabinoid receptor 2 mediates the retention of immature B cells in bone marrow sinusoids. Nat Immunol2009; 10: 403–411.
12.
IdrisAISophocleousALandao-BassongaE: Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor. Endocrinology2008; 149: 5619–5626.
13.
IdrisAIvan't HofRJGreigIR: Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med2005; 11: 774–779.
RossiFSiniscalcoDLuongoL: The endovanilloid/endocannabinoid system in human osteoclasts: Possible involvement in bone formation and resorption. Bone2009; 44: 476–484.
16.
LiuFZhuZMaoY: Inhibition of titanium particle-induced osteoclastogenesis through inactivation of NFATc1 by VIVIT peptide. Biomaterials2009; 30: 1756–1762.
17.
SmithMVLeeMJIslamAS: Inhibition of the PI3K-Akt signaling pathway reduces tumor necrosis factor-α production in response to titanium particles in vitro. J Bone Joint Surg Am2007; 89: 1019–1027.
18.
WooleyPHMorrenRAndaryJ: Inflammatory responses to orthopaedic biomaterials in the murine air pouch. Biomaterials2002; 23: 517–526.
19.
GengDXuYYangH: Protection against titanium particle induced osteolysis by cannabinoid receptor 2 selective antagonist. Biomaterials2010; 31: 1996–2000.
20.
KadoiYHinoharaHKunimotoF: Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats. Br J Anaesth2005; 94: 563–568.
21.
GengDCXuYZYangHL: Inhibition of titanium particle-induced inflammatory osteolysis through inactivation of cannabinoid receptor 2 by AM630. J Biomed Mater Res A2010; 95: 321–326.
22.
LivakKJSchmittgenTD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods2001; 25: 402–408.
23.
HarrisWH: Wear and periprosthetic osteolysis: The problem. Clin Orthop Relat Res2001; 393: 66–70.
GoodmanSBSongYYooJY: Local infusion of FGF-2 enhances bone ingrowth in rabbit chambers in the presence of polyethylene particles. J Biomed Mater Res A2003; 65: 454–461.
26.
MillettPJAllenMJBostromMP: Effects of alendronate on particle-induced osteolysis in a rat model. J Bone Joint Surg Am2002; 84-A: 236–249.
27.
RenWWuBPengX: Erythromycin inhibits wear particles-induced inflammatory osteolysis in a murine model. J Orthop Res2006; 24: 280–290.
28.
von KnochFHeckeleiAWedemeyerC: The effect of simvastatin on polyethylene particle-induced osteolysis. Biomaterials2005; 26: 3549–3555.
29.
RakshitDSLyKSenguptaTK: Wear debris inhibition of anti-osteoclastogenic signaling by interleukin-6 and interferon-γ. Mechanistic insights and implications for periprosthetic osteolysis. J Bone Joint Surg Am2006; 88: 788–799.
30.
RenWYangSYFangHW: Distinct gene expression of receptor activator of nuclear factor-κB and rank ligand in the inflammatory response to variant morphologies of UHMWPE particles. Biomaterials2003; 24: 4819–4826.
31.
WilkinsonJMWilsonAGStockleyI: Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplasty. J Bone Miner Res2003; 18: 1995–2001.
32.
GreenTRFisherJStoneM: Polyethylene particles of a ‘critical size’ are necessary for the induction of cytokines by macrophages in vitro. Biomaterials1998; 19: 2297–2302.
33.
GonzálezOSmithRLGoodmanSB: Effect of size, concentration, surface area, and volume of polymethylmethacrylate particles on human macrophages in vitro. J Biomed Mater Res1996; 30: 463–473.
