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

Our plain-English summary of Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation, by L. Burton, D. Paget, N.B. Binder, et al (Journal of Orthopaedic Research, 2013).

The study

• Authors: L. Burton, D. Paget, N.B. Binder, K. Bohnert, B.J. Nestor, T.P. Sculco, L. Santambrogio, F.P. Ross, S.R. Goldring, P.E. Purdue
• Journal: Journal of Orthopaedic Research
• Published: 2013;31(1):73-80
• Cited by: 82 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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-1β) 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-1β 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 µCT. Phagocytosis of PMMA particles induces caspase-1 dependent release of IL-1β from human monocytes and mouse macrophages. Importantly, using macrophages from mice deficient in components of the NALP3 inflammasome, we show PMMA-induced IL-1β 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.

Copyright © 2012 Orthopaedic Research Society.

In plain English

This laboratory study looked at how particles worn off joint replacements may cause bone loss. It did not test asbestos. Asbestos appeared only as background, as one of several particles earlier research linked to the same immune pathway, the NALP3 inflammasome. The authors exposed human blood cells (monocytes) and mouse bone marrow cells to PMMA, a plastic used in orthopedics. They compared normal mouse cells with cells from mice lacking NALP3, ASC or caspase-1. PMMA alone caused small but detectable release of the inflammatory signal IL-1 beta from human cells, and much more when bacterial LPS was added with it. In mouse cells first primed with LPS, IL-1 beta release fell significantly when caspase or particle uptake was blocked, or when any of the three components was missing. When PMMA or Simplex bone cement particles were placed on mouse skulls, mice lacking caspase-1 had significantly less bone loss than normal mice, though some loss remained. Missing components did not significantly affect formation of bone-resorbing cells in culture. The authors concluded that this pathway plays an important role in such bone loss.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using cultured human and mouse immune cells, with drug blocking and genetically altered (knockout) mice, plus an animal experiment in which particles were placed on mouse skulls
• Who was studied: Monocytes from anonymous healthy human blood donors (number not stated); bone marrow macrophages from wild-type mice and from mice lacking NALP3, ASC, or caspase-1; caspase-1 deficient and wild-type mice for the skull experiment; work done at the Hospital for Special Surgery, New York
• Exposure: Orthopedic wear particles: polymethylmethacrylate (PMMA) particles in cell cultures, and PMMA or Simplex bone cement particles implanted over mouse skulls. Human monocytes received LPS, PMMA, or both together for 6 hours. Mouse macrophages were first primed with LPS before PMMA was added. ATP was used as a comparison stimulus. Asbestos was not studied; it is mentioned only in the background.
• Main results:
  • In human monocytes, PMMA particles alone caused small but detectable increases in released IL-1 beta. Co-treatment with LPS markedly increased IL-1 beta release in response to PMMA.
  • In LPS-primed mouse macrophages, the caspase inhibitor zVAD significantly inhibited PMMA-induced IL-1 beta production.
  • In LPS-primed mouse macrophages, blocking particle uptake with cytochalasin D also significantly inhibited PMMA-induced IL-1 beta, which the authors took to suggest that particle uptake (phagocytosis) is required.
  • In LPS-primed mouse macrophages lacking NALP3, ASC or caspase-1, PMMA-induced IL-1 beta production was significantly reduced compared with wild-type cells, without affecting IL-6 release.
  • The authors stated that substantial IL-1 beta release from human and mouse cells in response to PMMA in culture required prior priming with an inflammatory stimulus such as LPS.
  • Sham-operated mice of both strains that received saline without particles showed no bone resorption.
  • In the mouse skull model, bone loss caused by PMMA and Simplex particles was significantly reduced in caspase-1 deficient mice compared with wild-type mice.
  • Caspase-1 deficiency did not completely prevent particle-induced bone destruction.
  • Lack of NALP3, ASC or caspase-1 did not significantly affect formation of osteoclasts (bone-resorbing cells) in culture compared with wild-type cells.
• The authors' conclusion: The authors concluded that activation of the NALP3 inflammasome plays an important role in bone loss caused by orthopedic implant wear debris.

Topics

Medical terms in this study, explained in our Lexicon: Macrophage, Phagocytosis.

Related studies

• PKC/ROS-Mediated NLRP3 Inflammasome Activation Is Attenuated by Leishmania Zinc-Metalloprotease during Infection — M.T. Shio, J.G. Christian, et al. (2015)
• Vimentin regulates activation of the NLRP3 inflammasome — G. dos Santos, M.R. Rogel, et al. (2015)
• Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica — C. Dostert, V. Pétrilli, et al. (2008)
• Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism — J. Palomäki, E. Välimäki, et al. (2011)
• The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine — L. Baron, A. Gombault, et al. (2015)
• Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β — A.S. Yazdi, G. Guarda, et al. (2010)

Browse return to medical research.