Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan.
WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
Nat Commun. 2023 Aug 3;14(1):4417. doi: 10.1038/s41467-023-40094-3.
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.
胆脂瘤可能由鼓膜回缩引起，其特征为局部骨侵蚀难以控制，并随后导致听力损失和脑脓肿形成。然而，骨破坏的病理生理机制仍不清楚。在这里，我们对人胆脂瘤样本进行了单细胞 RNA 测序分析，鉴定出一种以丰富表达抑制素 βA 为特征的致病成纤维细胞亚群。我们证明激活素 A（抑制素 βA 的同源二聚体）促进破骨细胞分化。此外，在胆脂瘤的小鼠模型中，这些成纤维细胞中抑制素 βA/激活素 A 的缺失导致破骨细胞分化减少。此外，激活素 A 的拮抗剂卵泡抑素减少胆脂瘤中的破骨细胞生成和由此产生的骨质侵蚀。总之，这些发现表明，人胆脂瘤组织中存在的独特的激活素 A 产生成纤维细胞通过诱导局部破骨细胞生成导致骨破坏，提示这可能是一个潜在的治疗靶点。
