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Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction

Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-c...

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Autores principales: Shimizu, Kotaro, Kikuta, Junichi, Ohta, Yumi, Uchida, Yutaka, Miyamoto, Yu, Morimoto, Akito, Yari, Shinya, Sato, Takashi, Kamakura, Takefumi, Oshima, Kazuo, Imai, Ryusuke, Liu, Yu-Chen, Okuzaki, Daisuke, Hara, Tetsuya, Motooka, Daisuke, Emoto, Noriaki, Inohara, Hidenori, Ishii, Masaru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400591/
https://www.ncbi.nlm.nih.gov/pubmed/37537159
http://dx.doi.org/10.1038/s41467-023-40094-3
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author Shimizu, Kotaro
Kikuta, Junichi
Ohta, Yumi
Uchida, Yutaka
Miyamoto, Yu
Morimoto, Akito
Yari, Shinya
Sato, Takashi
Kamakura, Takefumi
Oshima, Kazuo
Imai, Ryusuke
Liu, Yu-Chen
Okuzaki, Daisuke
Hara, Tetsuya
Motooka, Daisuke
Emoto, Noriaki
Inohara, Hidenori
Ishii, Masaru
author_facet Shimizu, Kotaro
Kikuta, Junichi
Ohta, Yumi
Uchida, Yutaka
Miyamoto, Yu
Morimoto, Akito
Yari, Shinya
Sato, Takashi
Kamakura, Takefumi
Oshima, Kazuo
Imai, Ryusuke
Liu, Yu-Chen
Okuzaki, Daisuke
Hara, Tetsuya
Motooka, Daisuke
Emoto, Noriaki
Inohara, Hidenori
Ishii, Masaru
author_sort Shimizu, Kotaro
collection PubMed
description Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin βA /activin A in these fibroblasts results in decreased osteoclast differentiation in a murine model of cholesteatoma. Moreover, follistatin, an antagonist of activin A, reduces osteoclastogenesis and resultant bone erosion in cholesteatoma. Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis, suggesting a potential therapeutic target.
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spelling pubmed-104005912023-08-05 Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction Shimizu, Kotaro Kikuta, Junichi Ohta, Yumi Uchida, Yutaka Miyamoto, Yu Morimoto, Akito Yari, Shinya Sato, Takashi Kamakura, Takefumi Oshima, Kazuo Imai, Ryusuke Liu, Yu-Chen Okuzaki, Daisuke Hara, Tetsuya Motooka, Daisuke Emoto, Noriaki Inohara, Hidenori Ishii, Masaru Nat Commun Article Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin βA /activin A in these fibroblasts results in decreased osteoclast differentiation in a murine model of cholesteatoma. Moreover, follistatin, an antagonist of activin A, reduces osteoclastogenesis and resultant bone erosion in cholesteatoma. Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis, suggesting a potential therapeutic target. Nature Publishing Group UK 2023-08-03 /pmc/articles/PMC10400591/ /pubmed/37537159 http://dx.doi.org/10.1038/s41467-023-40094-3 Text en © The Author(s) 2023 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 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/) .
spellingShingle Article
Shimizu, Kotaro
Kikuta, Junichi
Ohta, Yumi
Uchida, Yutaka
Miyamoto, Yu
Morimoto, Akito
Yari, Shinya
Sato, Takashi
Kamakura, Takefumi
Oshima, Kazuo
Imai, Ryusuke
Liu, Yu-Chen
Okuzaki, Daisuke
Hara, Tetsuya
Motooka, Daisuke
Emoto, Noriaki
Inohara, Hidenori
Ishii, Masaru
Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
title Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
title_full Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
title_fullStr Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
title_full_unstemmed Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
title_short Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
title_sort single-cell transcriptomics of human cholesteatoma identifies an activin a-producing osteoclastogenic fibroblast subset inducing bone destruction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400591/
https://www.ncbi.nlm.nih.gov/pubmed/37537159
http://dx.doi.org/10.1038/s41467-023-40094-3
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