title: Smad4 is required to inhibit osteoclastogenesis and maintain bone mass.
abstract: Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGFβs inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGFβ1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls. TGFβ1-activation induced expression of Irf8 and Bcl6, both of which encode factors inhibiting osteoclastogenesis, by blocking their negative regulator, Prdm1, in osteoclasts in a Smad4-dependent manner. Reduced bone-mass and accelerated osteoclastogenesis seen in Smad4-cKO were abrogated by Prdm1 deletion. Administration of latent-TGFβ1-Fc to wild-type mice antagonized LPS-induced bone destruction in a model of activated osteoclast-mediated bone destruction. Thus, latent-TGFβ1-Fc could serve as a promising new therapeutic agent in bone diseases marked by excessive resorption.
authors.affiliation: Division of Oral and Maxillofacial surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.affiliation: Division of Oral and Maxillofacial surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Division of Oral and Maxillofacial surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Iwasaki
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8859, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yasui
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Advanced Therapy for Musculoskeletal Disorders, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Oike
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Department of Pharmacology, Showa University School of Dentistry, 1-5-8 Hatanodai, Sinagawa-ku, Tokyo 142-0033, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
authors.affiliation: Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, NICHD, National Institutes of Health, Bethesda, MD.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8859, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Division of Oral and Maxillofacial surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Kawana
authors.affiliation: Division of Oral and Maxillofacial surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Taneaki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Advanced Therapy for Musculoskeletal Disorders, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D015519:Bone Density; D002454:Cell Differentiation; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; D000099185:Interferon Regulatory Factor-8; C490010:Bcl6 protein, mouse; C513258:Prdm1 protein, mouse; C490810:Smad4 protein, mouse; C508961:Tgfb1 protein, mouse