Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation

Abstract

Activation of myeloid cells by orthopedic particulate debris is a key event in the pathogenesis of periprosthetic osteolysis and implant loosening after total joint replacement (TJR). Several lines of evidence implicate NACHT, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome-mediated production of interleukin 1 beta (IL-1b) in the pathogenesis of clinical disorders ascribable to foreign particulate materials, including asbestos, silica, and urate crystals. Recent reports indicate that orthopedic polymer products and metallic particulates and ions may activate the same pathway. Here, we investigated the contribution of the NALP3 inflammasome to the pathogenesis of peri-implant osteolysis. Pharmaceutical and genetic perturbations of caspase-1 and inflammasome components were used to assess the role of the NALP3 inflammasome in IL-1b production and osteoclast formation by human monocytes and mouse macrophages in response to polymethylmethacrylate (PMMA) particle phagocytosis. The role of caspase-1 in a mouse calvarial model of particle-mediated osteolysis was assessed using mCT. Phagocytosis of PMMA particles induces caspase-1 dependent release of IL-1b from human monocytes and mouse macrophages. Importantly, using macrophages from mice deficient in components of the NALP3 inflammasome, we show PMMA-induced IL-1b production is strictly dependent on these components. Mice lacking caspase-1, the sole effector of the NALP3 inflammasome, show reduced orthopedic wear particle-induced calvarial osteolysis compared to wild-type controls. Absence of NALP3 inflammasome components fails to alter osteoclast formation in vitro. Our findings identify the NALP3 inflammasome as a critical mediator of orthopedic wear-induced osteolysis and as a viable therapeutic target for the treatment of periprosthetic osteolysis. ß

Resin Monomers Act as Adjuvants in Ni-induced Allergic Dermatitis in vivo

“…Polymethylmethacrylate particles reportedly induce a release of IL-1β in human monocytes and mouse macrophages via inflammasome activation (Burton et al, 2013). In contrast to our finding, earlier findings indicate that HEMA does not stimulate the production of IL-1β in vitro in THP-1 macrophages, human gingival fibroblasts, and keratinocytes (Rakich et al, 1999;Moharamzadeh et al, 2007).…”

Inflammatory osteolysis: a conspiracy against bone

“…The prevalence of myeloid cell responses indicates that the NLRP3 inflammasome likely participates in prosthetic loosening, implicating crystalline particles in the pathogenesis of NLRP3-mediated diseases. Furthermore, calvarial bone resorption that is induced by polymethylmethacrylate (PMMA) particles is reduced in the absence of NLRP3 (143). The size and shape of metal alloys affect the amplitude of the inflammasome response (144).…”

The Pathology of Orthopedic Implant Failure Is Mediated by Innate Immune System Cytokines

“…Active Caspase-1 is required for the processing and subsequent release of active proinflammatory cytokines such as IL-1 β and IL-18 (and others) by cleaving intracellular pro-IL-1 β , pro-IL-18, and so forth into their mature forms, IL-1b and IL-18. As IL-1 β is one of the main cytokines for activation of osteolysis, an involvement in aseptic loosening is obvious, as a recent study has shown less osteolysis in caspase-1 knockout mice [68]. …”