title: Intercellular Communication between Keratinocytes and Fibroblasts Induces Local Osteoclast Differentiation: a Mechanism Underlying Cholesteatoma-Induced Bone Destruction.
abstract: Bone homeostasis is maintained by a balance in activity between bone-resorbing osteoclasts and bone-forming osteoblasts. Shifting the balance toward bone resorption causes osteolytic bone diseases such as rheumatoid arthritis and periodontitis. Osteoclast differentiation is regulated by receptor activator of nuclear factor κB ligand (RANKL), which, under some pathological conditions, is produced by T and B lymphocytes and synoviocytes. However, the mechanism underlying bone destruction in other diseases is little understood. Bone destruction caused by cholesteatoma, an epidermal cyst in the middle ear resulting from hyperproliferation of keratinizing squamous epithelium, can lead to lethal complications. In this study, we succeeded in generating a model for cholesteatoma, epidermal cyst-like tissue, which has the potential for inducing osteoclastogenesis in mice. Furthermore, an in vitro coculture system composed of keratinocytes, fibroblasts, and osteoclast precursors was used to demonstrate that keratinocytes stimulate osteoclast differentiation through the induction of RANKL in fibroblasts. Thus, this study demonstrates that intercellular communication between keratinocytes and fibroblasts is involved in the differentiation and function of osteoclasts, which may provide the molecular basis of a new therapeutic strategy for cholesteatoma-induced bone destruction.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan JST, CREST, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Imai
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Furuya
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Uenaka
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Morihana
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Itoi-Ochi
authors.affiliation: Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Inohara
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan JST, CREST, Tokyo, Japan mishii@icb.med.osaka-u.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
mesh_terms: D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D002781:Cholesteatoma / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse