Effects of NF-kappaB inhibitor on titanium particulate-induced inflammation in a murine model.
ABSTRACT Activation of nuclear factor kappa B (NF-kappaB) signaling in response to implant particulates may be critical in the pathogenesis of implant loosening after joint arthroplasty. The purpose of this study was to investigate the inhibitory effects of pyrrolidine dithiocarbamate (PDTC) in a murine model of inflammation induced by titanium (Ti) particulates.
Ti particulates were introduced into established air pouches on C57BL/6J mice. Mice were injected intraperitoneally with either high-dose PDTC (100 mg/kg) or low-dose PDTC (50 mg/kg). Mice without drug treatment, as well as mice injected with saline alone were included. Each group consisted of sixteen mice. The membranes and lavage fluid were harvested 2 d or 7 d after injection of particulate suspension for histological and molecular analysis.
Histologic analysis showed that PDTC reduced inflammatory responses in air pouches, that is, thinner membrane and decreased cellular infiltration. In addition, PDTC reduced the release of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in the lavage fluid or supernatant of homogenates as evaluated by ELISA.
These results suggest that PDTC inhibits Ti particulate-induced inflammatory responses in the murine model; thus it represents a promising therapeutic candidate for the prevention and treatment of implant loosening.
[show abstract] [hide abstract]
ABSTRACT: Wear debris-induced aseptic loosening is an inflammatory bone disorder, which compromises the long-term success of total joint replacement. Despite the extensive research and great progress in treating inflammation-induced osteolysis for inflammatory arthritis, no drug has been proven for treatment/prevention of aseptic implant loosening. Also, there is very limited research on developing effective drug delivery systems for this pathological condition. In this review, we will discuss different therapeutic interventions and various delivery systems that have been developed for aseptic implant loosening. To provide the prospective for the future research in this area, the biology of wear particles-induced osteolysis, animal models developed for aseptic implant loosening and the potential challenges the field is facing are also presented in the discussion. Abbreviations: AAV, adeno-associated virus; ASO, antisense oligonucleotide; COX, cyclooxygenase; Dex, dexmethasone; ELVIS, extravasation through leaky vasculature and inflammatory cell-mediated sequestration; EM, erythromycin; FGF-2, fibroblast growth factor-2; FLS, fibroblast-like synoviocytes; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; HPMA, N-(2-hydroxypropyl) methacrylamide; IKK, IkBa kinase; IL, interleukin; IRDye, infrared dye; IkBa, inhibitor of nuclear factor kappa B alpha; LacZ, b-galactosidase; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; NEMO, NF-kB essential modulator; NF-kB, nuclear factor kappa B; OPG, osteoprotegerin; PAMAM, poly(amidoamine) dendrimer; P-Dex, HPMA copolymer–dexamethasone conjugate; PET, positron emission tomography; PGE 2 , prostaglandin E 2 ; PLGA, poly(lactic-co-glycolic acid); PMMA, poly(methyl methacrylate); RANK(L), receptor activator of nuclear factor kappa B (ligand); TGF-b, transforming growth factor beta; TNF, tumor necrosis factor; TRAP, tartrate-resistant acid phosphatase; UHMWPE, ultra-high-molecular-weight polyethylene; V-ATPases, vacuolar adenosine triphosphatase (Dong Wang). Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Acta Pharmaceutica Sinica B 2013;3(2):76–85