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

Lyndsey Burton, Daniel Paget, Nikolaus B. Binder, Krista Bohnert, Bryan J. Nestor, Thomas P. Sculco, Laura Santambrogio, F. Patrick Ross, Steven R. Goldring, P. Edward Purdue

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 ÂμCT. 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.

Original languageEnglish (US)
Pages (from-to)73-80
Number of pages8
JournalJournal of Orthopaedic Research
Volume31
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Inflammasomes
Osteolysis
Orthopedics
Caspase 1
Interleukin-1beta
Polymethyl Methacrylate
Macrophages
Osteoclasts
Phagocytosis
Monocytes
Replacement Arthroplasties
Asbestos
Myeloid Cells
Uric Acid
Silicon Dioxide
Polymers
Ions

Keywords

  • caspase-1
  • interleukin-1β
  • NALP3 inflammasome
  • periprosthetic osteolysis

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

Cite this

Burton, L., Paget, D., Binder, N. B., Bohnert, K., Nestor, B. J., Sculco, T. P., ... Purdue, P. E. (2013). Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation. Journal of Orthopaedic Research, 31(1), 73-80. https://doi.org/10.1002/jor.22190

Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation. / Burton, Lyndsey; Paget, Daniel; Binder, Nikolaus B.; Bohnert, Krista; Nestor, Bryan J.; Sculco, Thomas P.; Santambrogio, Laura; Ross, F. Patrick; Goldring, Steven R.; Purdue, P. Edward.

In: Journal of Orthopaedic Research, Vol. 31, No. 1, 01.2013, p. 73-80.

Research output: Contribution to journalArticle

Burton, L, Paget, D, Binder, NB, Bohnert, K, Nestor, BJ, Sculco, TP, Santambrogio, L, Ross, FP, Goldring, SR & Purdue, PE 2013, 'Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation', Journal of Orthopaedic Research, vol. 31, no. 1, pp. 73-80. https://doi.org/10.1002/jor.22190
Burton, Lyndsey ; Paget, Daniel ; Binder, Nikolaus B. ; Bohnert, Krista ; Nestor, Bryan J. ; Sculco, Thomas P. ; Santambrogio, Laura ; Ross, F. Patrick ; Goldring, Steven R. ; Purdue, P. Edward. / Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation. In: Journal of Orthopaedic Research. 2013 ; Vol. 31, No. 1. pp. 73-80.
@article{3a1038857e33497eb63e1551aaef333c,
title = "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-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 {\^A}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.",
keywords = "caspase-1, interleukin-1β, NALP3 inflammasome, periprosthetic osteolysis",
author = "Lyndsey Burton and Daniel Paget and Binder, {Nikolaus B.} and Krista Bohnert and Nestor, {Bryan J.} and Sculco, {Thomas P.} and Laura Santambrogio and Ross, {F. Patrick} and Goldring, {Steven R.} and Purdue, {P. Edward}",
year = "2013",
month = "1",
doi = "10.1002/jor.22190",
language = "English (US)",
volume = "31",
pages = "73--80",
journal = "Journal of Orthopaedic Research",
issn = "0736-0266",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation

AU - Burton, Lyndsey

AU - Paget, Daniel

AU - Binder, Nikolaus B.

AU - Bohnert, Krista

AU - Nestor, Bryan J.

AU - Sculco, Thomas P.

AU - Santambrogio, Laura

AU - Ross, F. Patrick

AU - Goldring, Steven R.

AU - Purdue, P. Edward

PY - 2013/1

Y1 - 2013/1

N2 - 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 ÂμCT. 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.

AB - 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 ÂμCT. 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.

KW - caspase-1

KW - interleukin-1β

KW - NALP3 inflammasome

KW - periprosthetic osteolysis

UR - http://www.scopus.com/inward/record.url?scp=84870247923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870247923&partnerID=8YFLogxK

U2 - 10.1002/jor.22190

DO - 10.1002/jor.22190

M3 - Article

VL - 31

SP - 73

EP - 80

JO - Journal of Orthopaedic Research

JF - Journal of Orthopaedic Research

SN - 0736-0266

IS - 1

ER -