Ear today, gone tomorrow? A new discovery in a cause of inner-ear bone loss
Researchers from Osaka University show that the possible cause of local bone erosionin cholesteatomas are fibroblasts from the bone that express a protein called activin A
Osaka, Japan – Chronic inflammation of the middle ear can cause several problems andcomplications that can affect a person’s hearing and balance. One such problem is theformation of a cholesteatoma, which is an abnormal collection of cells in the ear that cancause bone erosion if left untreated. In turn, this can cause symptoms such as hearing
loss, dizziness, facial paralysis, and even a brain infection.
In a study published recently in Nature Communications, researchers from Osaka
University have revealed the cause of cholesteatomas, which may help in developing
new therapies for patients who are suffering from this disease.
Cholesteatomas are made up of cysts or bumps in the ear that consist of skin, collagenfibers, skin cells, fibroblasts, keratin, and dead tissue. There are many theories on how
these cholesteatomas can cause bone erosion, including the activation of cells
responsible for the breakdown of the minerals and matrix of the bone, the presence ofinflammatory markers and enzymes, and the accumulation and pressure from dead cells
and tissues in the ear; however, the exact mechanism for the creation of cholesteatomas
remains unknown. “A cholesteatoma can still return or happen again even after its
surgical removal, so it is important to know what is actually causing it,” says lead author
Kotaro Shimizu.

To investigate this, researchers looked at human cholesteatoma tissues that weresurgically removed from patients. A process called single-cell RNA sequencing analysis
was employed to identify cells responsible for triggering bone erosion; these were called
osteoclastogenic fibroblasts. This study demonstrated how these fibroblasts expressed
an abundant amount of activin A, a molecule that regulates different physiologic functionsof the body. The presence of activin A is said to cause bone erosion through a process
in which specialized cells initiate bone resorption through a process wherein the minerals
and matrix of the bones are broken down and absorbed by the body.
The researchers were successful in showing the relationship between activin A and bone

erosion in cholesteatoma. “Our study showed that targeting activin A is a potential
treatment in the management of cholesteatomas,” states senior author Masaru Ishii.
Currently in clinical settings, the only effective treatment for cholesteatomas is complete
surgical removal. However, the discovery of how a cholesteatoma can cause boneerosion in this study offers new hope for developing novel medical treatments as firstline management for cholesteatomas.
###The article, “Single-cell transcriptomics of human cholesteatoma identifies an activin Aproducing osteoclastogenic fibroblast subset inducing bone destruction,” was publishedin Nature Communications at DOI: https://doi.org/10.1038/s41467-023-40094-3

Summary: The researchers from Osaka University showed how bone erosion causedby cholesteatoma occurs. This study showed that a subset of cells called
osteoclastogenic fibroblasts expresses a protein, activin A, which causes the breakdownof the bones. Because of this discovery, novel medical treatments can be developed as
first-line management for cholesteatomas.
Tweet: The #erosion of #bones from a #cholesteatoma in the #ear is caused by a subset
of fibroblasts that expresses #activin A, a protein that facilitates the breakdown of boneminerals@osaka_univ_eTweet 2: Discovering how bones erode because of a cholesteatoma in the ear can help
researchers discover novel medical treatments without the need for surgery
Primary keyword: Health and medicine
Additional keywords: Hearing loss, inflammation, proinflammatory cytokines,
orthopedics

Fig. 1
Schematic of osteoclastogenesis induced by cholesteatoma fibroblasts expressing activin A.
IL-1β, PGE2, and TNF-α secreted from infiltrating CD45+ cells, particularly macrophages,
induced activin A-expressing pathogenic fibroblasts; the activin A acted in conjunction withRANKL to promote ectopic osteoclastogenesis.
License: CC BY
Credit: 2023, Masaru Ishii, Single-cell transcriptomics of human cholesteatoma identifies anactivin A-producing osteoclastogenic fibroblast subset inducing bone destruction, Nature
Communications

Fig. 2
Subclustering and pseudotime analysis of human cholesteatoma fibroblasts. Cholesteatoma
fibroblasts were associated with five subclusters labeled 1, 7, 8, 10, and 11 (right panel). The
most differentiated cells (labeled red) were identical to cholesteatoma fibroblasts insubcluster 8 (middle panel). Cholesteatoma fibroblasts showed high levels of INHBA
expression, and the area of high INHBA expression was identical to the area incholesteatoma fibroblasts in subcluster 8 (left panel).
License: CC BY
Credit: 2023, Masaru Ishii, Single-cell transcriptomics of human cholesteatoma identifies anactivin A-producing osteoclastogenic fibroblast subset inducing bone destruction, NatureCommunications

Fig. 3The in vivo role of activin A in osteoclastogenesis in an experimental mouse model ofcholesteatoma.
INHBA inhibition in fibroblasts reduced osteoclast formation on the parietal bone surface
under the cholesteatoma mass. Red, osteoclasts; green, parietal bone surface. Scale bars:
500 µm.
License: CC BY
Credit: 2023, Masaru Ishii, Single-cell transcriptomics of human cholesteatoma identifies anactivin A-producing osteoclastogenic fibroblast subset inducing bone destruction, Nature
Communications

Journal: Nature Communications
Title: Single-cell transcriptomics of human cholesteatoma identifies an activin Aproducing osteoclastogenic fibroblast subset inducing bone destruction
Authors: 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, NoriakiEmoto, Hidenori Inohara, and Masaru Ishii
DOI: 10.1038/s41467-023-40094-3
Funded by:
Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development
Japan Science and Technology Agency