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

Kotaro Shimizu, Junichi Kikuta (), Yumi Ohta, Yutaka Uchida, Yu Miyamoto, Akito Morimoto, Shinya Yari, Takashi Sato, Takefumi Kamakura, Kazuo Oshima, Ryusuke Imai, Yu-Chen Liu, Daisuke Okuzaki, Tetsuya Hara, Daisuke Motooka, Noriaki Emoto, Hidenori Inohara and Masaru Ishii ()
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Kotaro Shimizu: Osaka University
Junichi Kikuta: Osaka University
Yumi Ohta: Osaka University
Yutaka Uchida: Osaka University
Yu Miyamoto: Osaka University
Akito Morimoto: Osaka University
Shinya Yari: Osaka University
Takashi Sato: Osaka University
Takefumi Kamakura: Osaka University
Kazuo Oshima: Osaka University
Ryusuke Imai: Osaka University
Yu-Chen Liu: Osaka University
Daisuke Okuzaki: Osaka University
Tetsuya Hara: Kobe Pharmaceutical University
Daisuke Motooka: Osaka University
Noriaki Emoto: Kobe Pharmaceutical University
Hidenori Inohara: Osaka University
Masaru Ishii: Osaka University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40094-3

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DOI: 10.1038/s41467-023-40094-3

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