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Home  > Press Release  > Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

Highlights

•Estrogen suppressed the Sema3a-targeting miRNAs, thereby enhancing Sema3A expression

•Sema3A deficiency in osteocytes led to severe osteopenia in aged mice

•Sema3A-activated sGC-cGMP signaling protected osteocytes from apoptosis

•Serum levels of SEMA3A decreased with age or after menopause in humans

Summary

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.

Journal Article

JOURNAL:
Cell Metabolism
TITLE:
Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone
Aging
DOI:
https://doi.org/10.1016/j.cmet.2018.12.021

Correspondence to

Tomoki Nakashima, Ph.D., Professor
Department of Cell Signaling,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University(TMDU)
E-mail:t.naka.csi(at)tmd.ac.jp