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IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology

Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocyt...

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Autores principales: Arra, Manoj, Swarnkar, Gaurav, Alippe, Yael, Mbalaviele, Gabriel, Abu-Amer, Yousef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831569/
https://www.ncbi.nlm.nih.gov/pubmed/35145063
http://dx.doi.org/10.1038/s41413-021-00183-9
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author Arra, Manoj
Swarnkar, Gaurav
Alippe, Yael
Mbalaviele, Gabriel
Abu-Amer, Yousef
author_facet Arra, Manoj
Swarnkar, Gaurav
Alippe, Yael
Mbalaviele, Gabriel
Abu-Amer, Yousef
author_sort Arra, Manoj
collection PubMed
description Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their role was not defined. We further show that bone particles and IL-1β can promote senescent and apoptotic changes in primary chondrocytes due to oxidative stress from various cellular sources such as the mitochondria. Finally, we provide evidence that inflammation, oxidative stress and senescence converge upon IκB-ζ, the principal mediator downstream of NF-κB, which regulates expression of RANKL, inflammatory, catabolic, and SASP genes. Overall, this work highlights the capacity and mechanisms by which inflammatory cues, primarily joint degradation products, i.e., bone matrix particles in concert with IL-1β in the joint microenvironment, program chondrocytes into an “inflammatory phenotype” which inflects local tissue damage.
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spelling pubmed-88315692022-02-24 IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology Arra, Manoj Swarnkar, Gaurav Alippe, Yael Mbalaviele, Gabriel Abu-Amer, Yousef Bone Res Article Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their role was not defined. We further show that bone particles and IL-1β can promote senescent and apoptotic changes in primary chondrocytes due to oxidative stress from various cellular sources such as the mitochondria. Finally, we provide evidence that inflammation, oxidative stress and senescence converge upon IκB-ζ, the principal mediator downstream of NF-κB, which regulates expression of RANKL, inflammatory, catabolic, and SASP genes. Overall, this work highlights the capacity and mechanisms by which inflammatory cues, primarily joint degradation products, i.e., bone matrix particles in concert with IL-1β in the joint microenvironment, program chondrocytes into an “inflammatory phenotype” which inflects local tissue damage. Nature Publishing Group UK 2022-02-11 /pmc/articles/PMC8831569/ /pubmed/35145063 http://dx.doi.org/10.1038/s41413-021-00183-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Arra, Manoj
Swarnkar, Gaurav
Alippe, Yael
Mbalaviele, Gabriel
Abu-Amer, Yousef
IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
title IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
title_full IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
title_fullStr IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
title_full_unstemmed IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
title_short IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
title_sort iκb-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831569/
https://www.ncbi.nlm.nih.gov/pubmed/35145063
http://dx.doi.org/10.1038/s41413-021-00183-9
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