Chronic inflammation of the middle ear can cause several problems and complications that can affect a person’s hearing and balance. One such problem is the formation of a cholesteatoma, which is an abnormal collection of cells in the ear that can lead to bone erosion if left untreated. In turn, this can cause symptoms such as hearing loss, dizziness, facial paralysis, and even a brain infection.

Researchers from Osaka University just published a study “Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction” in Nature Communications that describes the cause of cholesteatomas, which may help in developing new therapies for patients who are suffering from this disease.

Schematic of osteoclastogenesis induced by cholesteatoma fibroblasts expressing activin A. Proinflammatory cytokines secreted from infiltrating macrophages induced activin A-expressing pathogenic fibroblasts; the activin A acted in conjunction with RANKL to promote ectopic osteoclastogenesis. [2023, Masaru Ishii, Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction, [Nature Communications].

“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,” write the investigators.

“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.”

Single-cell RNA sequencing

The Osaka team looked at human cholesteatoma tissues that were surgically removed from patients. 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 functions of 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,” says senior author Masaru Ishii, MD, PhD, professor.

Currently in clinical settings, the only effective treatment for cholesteatomas is complete surgical removal. However, the discovery of how a cholesteatoma can cause bone erosion in this study offers new hope for developing novel medical treatments as first-line management for cholesteatomas.

“A cholesteatoma can still return or happen again even after its surgical removal, so it is important to know what is actually causing it,” notes lead author Kotaro Shimizu.

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