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Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage

BACKGROUND: Osteoarthritis (OA) is a debilitating disease involving cartilage degradation. A need remains for the discovery of new molecular targets in cartilage for pharmaceutical intervention of OA. One potential target is integrin α1β1 that protects against OA when it is upregulated by chondrocyt...

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Autores principales: Black, Alicia L., Haskins, James, Pozzi, Ambra, Clark, Andrea L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9987067/
https://www.ncbi.nlm.nih.gov/pubmed/36879303
http://dx.doi.org/10.1186/s13018-023-03655-2
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author Black, Alicia L.
Haskins, James
Pozzi, Ambra
Clark, Andrea L.
author_facet Black, Alicia L.
Haskins, James
Pozzi, Ambra
Clark, Andrea L.
author_sort Black, Alicia L.
collection PubMed
description BACKGROUND: Osteoarthritis (OA) is a debilitating disease involving cartilage degradation. A need remains for the discovery of new molecular targets in cartilage for pharmaceutical intervention of OA. One potential target is integrin α1β1 that protects against OA when it is upregulated by chondrocytes early in the disease process. Integrin α1β1 offers this protection by dampening epidermal growth factor receptor (EGFR) signaling, and its effects are more robust in females compared to males. The aim of this study, therefore, was to measure the impact of itga1 on chondrocyte EGFR activity and downstream reactive oxygen species (ROS) production in male and female mice. Furthermore, chondrocyte expression of estrogen receptor (ER) α and ERβ was measured to investigate the mechanism for sexual dimorphism in the EGFR/integrin α1β1 signaling axis. We hypothesized that integrin α1β1 would decrease ROS production and pEGFR and 3-nitrotyrosine expression, with this effect being greater in females. We further hypothesized that chondrocyte expression of ERα and ERβ would be greater in females compared to males, with a greater effect seen in itga1-null compared to wild-type mice. MATERIALS AND METHODS: Femoral and tibial cartilage of male and female, wild-type and itga1-null mice were processed for ex vivo confocal imaging of ROS, immunohistochemical analysis of 3-nitrotyrosine, or immunofluorescence of pEGFR and ERα and ERβ. RESULTS: We show that ROS-producing chondrocytes are more abundant in female itga1-null compared to wild-type mice ex vivo; however, itga1 had limited influence on the percent of chondrocytes stained positively for 3-nitrotyrosine or pEGFR in situ. In addition, we found that itga1 influenced ERα and ERβ expression in femoral cartilage from female mice, and that ERα and ERβ were coexpressed as well as colocalized in chondrocytes. Finally, we show sexual dimorphism in ROS and 3-nitrotyrosine production, but surprisingly not in pEGFR expression. CONCLUSIONS: Together these data highlight sexual dimorphism in the EGFR/integrin α1β1 signaling axis and underline the need for further investigation into the role of ERs in this biological paradigm. Understanding the molecular mechanisms underlying the development of OA is essential for the development of individualized, sex-specific treatments in this age of personalized medicine.
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spelling pubmed-99870672023-03-07 Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage Black, Alicia L. Haskins, James Pozzi, Ambra Clark, Andrea L. J Orthop Surg Res Research Article BACKGROUND: Osteoarthritis (OA) is a debilitating disease involving cartilage degradation. A need remains for the discovery of new molecular targets in cartilage for pharmaceutical intervention of OA. One potential target is integrin α1β1 that protects against OA when it is upregulated by chondrocytes early in the disease process. Integrin α1β1 offers this protection by dampening epidermal growth factor receptor (EGFR) signaling, and its effects are more robust in females compared to males. The aim of this study, therefore, was to measure the impact of itga1 on chondrocyte EGFR activity and downstream reactive oxygen species (ROS) production in male and female mice. Furthermore, chondrocyte expression of estrogen receptor (ER) α and ERβ was measured to investigate the mechanism for sexual dimorphism in the EGFR/integrin α1β1 signaling axis. We hypothesized that integrin α1β1 would decrease ROS production and pEGFR and 3-nitrotyrosine expression, with this effect being greater in females. We further hypothesized that chondrocyte expression of ERα and ERβ would be greater in females compared to males, with a greater effect seen in itga1-null compared to wild-type mice. MATERIALS AND METHODS: Femoral and tibial cartilage of male and female, wild-type and itga1-null mice were processed for ex vivo confocal imaging of ROS, immunohistochemical analysis of 3-nitrotyrosine, or immunofluorescence of pEGFR and ERα and ERβ. RESULTS: We show that ROS-producing chondrocytes are more abundant in female itga1-null compared to wild-type mice ex vivo; however, itga1 had limited influence on the percent of chondrocytes stained positively for 3-nitrotyrosine or pEGFR in situ. In addition, we found that itga1 influenced ERα and ERβ expression in femoral cartilage from female mice, and that ERα and ERβ were coexpressed as well as colocalized in chondrocytes. Finally, we show sexual dimorphism in ROS and 3-nitrotyrosine production, but surprisingly not in pEGFR expression. CONCLUSIONS: Together these data highlight sexual dimorphism in the EGFR/integrin α1β1 signaling axis and underline the need for further investigation into the role of ERs in this biological paradigm. Understanding the molecular mechanisms underlying the development of OA is essential for the development of individualized, sex-specific treatments in this age of personalized medicine. BioMed Central 2023-03-06 /pmc/articles/PMC9987067/ /pubmed/36879303 http://dx.doi.org/10.1186/s13018-023-03655-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Black, Alicia L.
Haskins, James
Pozzi, Ambra
Clark, Andrea L.
Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
title Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
title_full Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
title_fullStr Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
title_full_unstemmed Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
title_short Sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
title_sort sexual dimorphism in reactive oxygen species production and a role for integrin α1β1 in estrogen receptor α and β expression in articular cartilage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9987067/
https://www.ncbi.nlm.nih.gov/pubmed/36879303
http://dx.doi.org/10.1186/s13018-023-03655-2
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