Osteoclasts Modulate Bone Erosion in Cholesteatoma via RANKL Signaling
Cholesteatoma starts as a retraction of the tympanic membrane and expands into the middle ear, eroding the surrounding bone and causing hearing loss and other serious complications such as brain abscess and meningitis. Currently, the only effective treatment is complete surgical removal, but the recurrence rate is relatively high. In rheumatoid arthritis (RA), osteoclasts are known to be responsible for bone erosion and undergo differentiation and activation by receptor activator of NF-κB ligand (RANKL), which is secreted by synovial fibroblasts, T cells, and B cells. On the other hand, the mechanism of bone erosion in cholesteatoma is still controversial. In this study, we found that a significantly larger number of osteoclasts were observed on the eroded bone adjacent to cholesteatomas than in unaffected areas, and that fibroblasts in the cholesteatoma perimatrix expressed RANKL. We also investigated upstream transcription factors of RANKL using RNA sequencing results obtained via Ingenuity Pathways Analysis, a tool that identifies relevant targets in molecular biology systems. The concentrations of four candidate factors, namely interleukin-1β, interleukin-6, tumor necrosis factor α, and prostaglandin E2, were increased in cholesteatomas compared with normal skin. Furthermore, interleukin-1β was expressed in infiltrating inflammatory cells in the cholesteatoma perimatrix. This is the first report demonstrating that a larger-than-normal number of osteoclasts are present in cholesteatoma, and that the disease involves upregulation of factors related to osteoclast activation. Our study elucidates the molecular basis underlying bone erosion in cholesteatoma.
Keywordscholesteatoma osteoclast fibroblast receptor activator of NF-κB ligand (RANKL) RNA sequencing IL-1β
We would like to thank Dr. Hiroyuki Murota, Dr. Mari Kaneda, Dr. Saori Ochi, Dr. Takefumi Kamakura, and Dr. Yohei Maeda for the helpful discussions, and Ms. Yumiko Fujii and Ms. Sayaka Matsumura for research assistance.
This work was supported by a JSPS KAKENHI Grant (nos. JP16K20242).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
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