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Smad4 is required to inhibit osteoclastogenesis and maintain bone mass
Morita M.1; Yoshida S.1; Iwasaki R.1; Yasui T.4; Sato Y.1; Kobayashi T.1; Watanabe R.1; Oike T.1; Miyamoto K.1; Takami M.5; Ozato K.3; Deng C.-X.6; Aburatani H.2; Tanaka S.4; Yoshimura A.1; Toyama Y.1; Matsumoto M.1; Nakamura M.1; Kawana H.1; Nakagawa T.1; Miyamoto T.1
2016-10-12
Source PublicationScientific Reports
ISSN20452322
Volume6
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.

DOI10.1038/srep35221
URLView the original
Indexed BySCI
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000385001100001
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Co-First AuthorMorita M.; Yoshida S.
Corresponding AuthorMiyamoto T.
Affiliation1.Keio University
2.University of Tokyo, Research Center for Advanced Science and Technology
3.National Institutes of Health, Bethesda
4.University of Tokyo
5.Showa University
6.Universidade de Macau
Recommended Citation
GB/T 7714
Morita M.,Yoshida S.,Iwasaki R.,et al. Smad4 is required to inhibit osteoclastogenesis and maintain bone mass[J]. Scientific Reports,2016,6.
APA Morita M..,Yoshida S..,Iwasaki R..,Yasui T..,Sato Y..,...&Miyamoto T..(2016).Smad4 is required to inhibit osteoclastogenesis and maintain bone mass.Scientific Reports,6.
MLA Morita M.,et al."Smad4 is required to inhibit osteoclastogenesis and maintain bone mass".Scientific Reports 6(2016).
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