Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

doi:10.1016/j.cmet.2018.12.021

. 2019 Mar 5;29(3):627-637.e5.

doi: 10.1016/j.cmet.2018.12.021. Epub 2019 Jan 17.

Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

Mikihito Hayashi¹, Tomoki Nakashima², Noriko Yoshimura³, Kazuo Okamoto⁴, Sakae Tanaka⁵, Hiroshi Takayanagi⁶

Affiliations

¹ Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
² Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo 113-8549, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 113-8549, Japan. Electronic address: naka.csi@tmd.ac.jp.
³ Department of Joint Disease Research, 22nd Century Medical and Research Center, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁴ Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁵ Department of Orthopedic Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁶ Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: takayana@m.u-tokyo.ac.jp.

PMID: 30661929
DOI: 10.1016/j.cmet.2018.12.021

Free article

Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

Mikihito Hayashi et al. Cell Metab. 2019.

Free article

. 2019 Mar 5;29(3):627-637.e5.

doi: 10.1016/j.cmet.2018.12.021. Epub 2019 Jan 17.

Authors

Mikihito Hayashi¹, Tomoki Nakashima², Noriko Yoshimura³, Kazuo Okamoto⁴, Sakae Tanaka⁵, Hiroshi Takayanagi⁶

Affiliations

¹ Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
² Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo 113-8549, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 113-8549, Japan. Electronic address: naka.csi@tmd.ac.jp.
³ Department of Joint Disease Research, 22nd Century Medical and Research Center, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁴ Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁵ Department of Orthopedic Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁶ Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: takayana@m.u-tokyo.ac.jp.

PMID: 30661929
DOI: 10.1016/j.cmet.2018.12.021

Abstract

Osteocyte survival is key to bone homeostasis and is perturbed in menopause and aging. However, it remains unknown how osteocyte-mediated maintenance of the skeleton is regulated by the osteoprotective factor semaphorin 3A (Sema3A), a secreted protein that is known to reduce bone resorption and enhance bone formation. Here, we show that estrogen induces osteocyte expression of Sema3A, which acts on its receptor on osteocytes to promote their survival and maintain bone homeostasis. Postnatal global and conditional deletion of Sema3a in osteoblastic cells resulted in a severe osteoporotic phenotype marked by fewer osteocytes. This phenotype was recapitulated by osteocyte-specific deficiency of either Sema3A or its receptor component neuropilin-1 (Nrp1). A stimulator of soluble guanylate cyclase-cGMP signaling mimicked Sema3A action and ameliorated bone loss after ovariectomy. We further show that serum levels of SEMA3A decreased with age or after menopause in humans. Thus, we provide a mechanistic insight into the estrogen action and a promising therapeutic approach to protect against bone-related aging.

Keywords: Sema3A; bone aging; osteocyte.

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Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

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Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

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