Journal
CELL METABOLISM
Volume 29, Issue 3, Pages 627-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.12.021
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Funding
- Japan Science and Technology Agency [JPMJPR13MC]
- AMED-CREST, AMED [JP17gm0810003]
- Japan Society for the Promotion of Science (JSPS)
- Mochida Memorial Foundation
- Terumo Foundation
- Life Science Foundation of Japan
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ichiro Kanehara Foundation
- Kanazawa Medical Research Foundation
- Naito Foundation
- Nakatomi Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Sumitomo Foundation
- Asahi Glass Foundation
- Mitsui Life Social Welfare Foundation
- Daiichi Sankyo Foundation
- ONO Medical Research Foundation
- Secom Science and Technology Foundation
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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.
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