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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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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. |
format | Online Article Text |
id | pubmed-8831569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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