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THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia
Disclosure: T. You: None. H. Zhao: None. T. Potluri: None. P. Yin: None. S.E. Bulun: None. Inguinal hernias affect up to 27% of elderly men, with approximately 800,000 inguinal hernia repair surgeries performed annually. While these procedures are often effective, a significant subset of hernias are...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555426/ http://dx.doi.org/10.1210/jendso/bvad114.1719 |
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author | You, Tianming Zhao, Hong Potluri, Tanvi Yin, Ping Ekrem Bulun, Serdar |
author_facet | You, Tianming Zhao, Hong Potluri, Tanvi Yin, Ping Ekrem Bulun, Serdar |
author_sort | You, Tianming |
collection | PubMed |
description | Disclosure: T. You: None. H. Zhao: None. T. Potluri: None. P. Yin: None. S.E. Bulun: None. Inguinal hernias affect up to 27% of elderly men, with approximately 800,000 inguinal hernia repair surgeries performed annually. While these procedures are often effective, a significant subset of hernias are refractory to treatment, resulting in high mortality, high recurrence, and chronic pain. Until recently, little research has been done examining the molecular mechanisms that drive hernia-associated lower abdominal wall weakening. Our lab previously created a transgenic mouse model expressing the human aromatase gene (Arom(hum)) and showed that male Arom(hum) mice produced high levels of estrogen in the lower abdominal muscle (LAM) tissue, leading to extensive LAM fibrosis, muscle atrophy, and hernia formation. Single-cell analysis of fibrotic LAM tissue in these mice showed high expression of estrogen receptor alpha (ERα) in LAM fibroblasts as well as upregulation of Wnt signaling pathways in these ERα-positive fibroblasts. The canonical Wnt/β-catenin signaling pathway has been implicated in fibroblast activation and fibrosis in multiple organs, including the lung, heart, and skin. Thus, we hypothesized that canonical Wnt/β-catenin signaling acts as a downstream mediator of ERα to cause LAM fibroblast activation, tissue fibrosis, and hernia. To test our hypothesis, we cultured primary ERα-positive LAM fibroblasts from Arom(hum) mice in the presence of estrogen with or without siRNA knockdown (KD) of β-catenin. However, KD of β-catenin under these conditions did not alter fibroblast proliferation as measured by EdU assay, nor did it alter expression of genes involved in fibroblast activation or extracellular matrix formation. Furthermore, administration of LGK974, a Wnt signaling inhibitor, in male Arom(hum) mice did not prevent hernia development, decrease hernia size, or decrease the extent of LAM fibrosis and muscle atrophy. Thus, we concluded that the canonical Wnt/β-catenin signaling pathway does not serve as a downstream mediator of estrogen-induced skeletal muscle fibrosis in our Arom(hum) mouse model of inguinal hernia. Further studies are needed to evaluate the role of Wnt/β-catenin signaling in other inguinal hernia models or in humans. Presentation Date: Thursday, June 15, 2023 |
format | Online Article Text |
id | pubmed-10555426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105554262023-10-06 THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia You, Tianming Zhao, Hong Potluri, Tanvi Yin, Ping Ekrem Bulun, Serdar J Endocr Soc Steroid Hormones, Nuclear Receptors and Coregulators Disclosure: T. You: None. H. Zhao: None. T. Potluri: None. P. Yin: None. S.E. Bulun: None. Inguinal hernias affect up to 27% of elderly men, with approximately 800,000 inguinal hernia repair surgeries performed annually. While these procedures are often effective, a significant subset of hernias are refractory to treatment, resulting in high mortality, high recurrence, and chronic pain. Until recently, little research has been done examining the molecular mechanisms that drive hernia-associated lower abdominal wall weakening. Our lab previously created a transgenic mouse model expressing the human aromatase gene (Arom(hum)) and showed that male Arom(hum) mice produced high levels of estrogen in the lower abdominal muscle (LAM) tissue, leading to extensive LAM fibrosis, muscle atrophy, and hernia formation. Single-cell analysis of fibrotic LAM tissue in these mice showed high expression of estrogen receptor alpha (ERα) in LAM fibroblasts as well as upregulation of Wnt signaling pathways in these ERα-positive fibroblasts. The canonical Wnt/β-catenin signaling pathway has been implicated in fibroblast activation and fibrosis in multiple organs, including the lung, heart, and skin. Thus, we hypothesized that canonical Wnt/β-catenin signaling acts as a downstream mediator of ERα to cause LAM fibroblast activation, tissue fibrosis, and hernia. To test our hypothesis, we cultured primary ERα-positive LAM fibroblasts from Arom(hum) mice in the presence of estrogen with or without siRNA knockdown (KD) of β-catenin. However, KD of β-catenin under these conditions did not alter fibroblast proliferation as measured by EdU assay, nor did it alter expression of genes involved in fibroblast activation or extracellular matrix formation. Furthermore, administration of LGK974, a Wnt signaling inhibitor, in male Arom(hum) mice did not prevent hernia development, decrease hernia size, or decrease the extent of LAM fibrosis and muscle atrophy. Thus, we concluded that the canonical Wnt/β-catenin signaling pathway does not serve as a downstream mediator of estrogen-induced skeletal muscle fibrosis in our Arom(hum) mouse model of inguinal hernia. Further studies are needed to evaluate the role of Wnt/β-catenin signaling in other inguinal hernia models or in humans. Presentation Date: Thursday, June 15, 2023 Oxford University Press 2023-10-05 /pmc/articles/PMC10555426/ http://dx.doi.org/10.1210/jendso/bvad114.1719 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Steroid Hormones, Nuclear Receptors and Coregulators You, Tianming Zhao, Hong Potluri, Tanvi Yin, Ping Ekrem Bulun, Serdar THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia |
title | THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia |
title_full | THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia |
title_fullStr | THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia |
title_full_unstemmed | THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia |
title_short | THU575 The Canonical Wnt/β-catenin Pathway Is Not Involved In Estrogen-induced Skeletal Muscle Fibrosis In A Mouse Model Of Inguinal Hernia |
title_sort | thu575 the canonical wnt/β-catenin pathway is not involved in estrogen-induced skeletal muscle fibrosis in a mouse model of inguinal hernia |
topic | Steroid Hormones, Nuclear Receptors and Coregulators |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555426/ http://dx.doi.org/10.1210/jendso/bvad114.1719 |
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