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- Title
Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction.
- Authors
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
- 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. This study identified a subset of osteoclastogenic fibroblasts expressing INHBA/activin A in human cholesteatoma. It further elucidated the mechanism behind the induction of inflammatory bone destruction, suggesting a potential therapeutic target.
- Subjects
CHOLESTEATOMA; INHIBIN; ACTIVIN; TYMPANIC membrane; FIBROBLASTS; BRAIN abscess
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40094-3