Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and syst...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338787/ https://www.ncbi.nlm.nih.gov/pubmed/22558291 http://dx.doi.org/10.1371/journal.pone.0035979 |
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author | Bonar, Sheri L. Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla Chen, Debbie Grimston, Susan K. Hickman-Brecks, Cynthia L. Ravindran, Soumya McAlinden, Audrey Novack, Deborah V. Kastner, Daniel L. Civitelli, Roberto Hoffman, Hal M. Mbalaviele, Gabriel |
author_facet | Bonar, Sheri L. Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla Chen, Debbie Grimston, Susan K. Hickman-Brecks, Cynthia L. Ravindran, Soumya McAlinden, Audrey Novack, Deborah V. Kastner, Daniel L. Civitelli, Roberto Hoffman, Hal M. Mbalaviele, Gabriel |
author_sort | Bonar, Sheri L. |
collection | PubMed |
description | The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling. |
format | Online Article Text |
id | pubmed-3338787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33387872012-05-03 Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice Bonar, Sheri L. Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla Chen, Debbie Grimston, Susan K. Hickman-Brecks, Cynthia L. Ravindran, Soumya McAlinden, Audrey Novack, Deborah V. Kastner, Daniel L. Civitelli, Roberto Hoffman, Hal M. Mbalaviele, Gabriel PLoS One Research Article The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling. Public Library of Science 2012-04-27 /pmc/articles/PMC3338787/ /pubmed/22558291 http://dx.doi.org/10.1371/journal.pone.0035979 Text en Bonar et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Bonar, Sheri L. Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla Chen, Debbie Grimston, Susan K. Hickman-Brecks, Cynthia L. Ravindran, Soumya McAlinden, Audrey Novack, Deborah V. Kastner, Daniel L. Civitelli, Roberto Hoffman, Hal M. Mbalaviele, Gabriel Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice |
title | Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice |
title_full | Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice |
title_fullStr | Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice |
title_full_unstemmed | Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice |
title_short | Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice |
title_sort | constitutively activated nlrp3 inflammasome causes inflammation and abnormal skeletal development in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338787/ https://www.ncbi.nlm.nih.gov/pubmed/22558291 http://dx.doi.org/10.1371/journal.pone.0035979 |
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