Smad4 is required to inhibit osteoclastogenesis and maintain bone mass

Mayu Morita, Shigeyuki Yoshida, Ryotaro Iwasaki, Tetsuro Yasui, Yuiko Sato, Tami Kobayashi, Ryuichi Watanabe, Takatsugu Oike, Kana Miyamoto, Masamichi Takami, Keiko Ozato, Chu Xia Deng, Hiroyuki Aburatani, Sakae Tanaka, Akihiko Yoshimura, Yoshiaki Toyama, Morio Matsumoto, Masaya Nakamura, Hiromasa Kawana, Taneaki NakagawaTakeshi Miyamoto

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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.

Original languageEnglish
Article number35221
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Oct 12

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Cite this

Morita, M., Yoshida, S., Iwasaki, R., Yasui, T., Sato, Y., Kobayashi, T., Watanabe, R., Oike, T., Miyamoto, K., Takami, M., Ozato, K., Deng, C. X., Aburatani, H., Tanaka, S., Yoshimura, A., Toyama, Y., Matsumoto, M., Nakamura, M., Kawana, H., ... Miyamoto, T. (2016). Smad4 is required to inhibit osteoclastogenesis and maintain bone mass. Scientific Reports, 6, [35221]. https://doi.org/10.1038/srep35221