RRC ID 54417
Author Hayashi M, Nakashima T, Yoshimura N, Okamoto K, Tanaka S, Takayanagi H.
Title Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging.
Journal Cell Metab
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.
Volume 29(3)
Pages 627-637.e5
Published 2019-3-5
DOI 10.1016/j.cmet.2018.12.021
PII S1550-4131(18)30758-7
PMID 30661929
MeSH Aging / metabolism* Animals Bone Resorption / metabolism Estrogens / metabolism* Female HEK293 Cells Humans Menopause / metabolism* Mice Mice, Inbred C57BL Middle Aged Neuropilin-1 / metabolism Osteocytes / cytology Osteocytes / metabolism* Osteogenesis / physiology Semaphorin-3A / physiology*
IF 22.415
Times Cited 19
Mice RBRC01106
Human and Animal Cells 293(RCB1637)