Cited by 157Bone Metabolism and DiseasesBone health and osteoporosis researchMedicinal Plant Pharmacodynamics Research

Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging

Open access
Hayashi, Mikihito, Nakashima, Tomoki, Yoshimura, Noriko, Okamoto, Kazuo, Tanaka, Sakae, Takayanagi, Hiroshi·2019·Cell Metabolism

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.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2018.12.021

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Hayashi, M., Nakashima, T., Yoshimura, N., Okamoto, K., Tanaka, S., & Takayanagi, H.
Affiliations
  • Tokyo Medical and Dental University (JP)
  • The University of Tokyo (JP)
Corresponding author
  • Nakashima, Tomoki
  • Takayanagi, Hiroshi
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2019-03
Volume
29
Issue
3
Pages
627-637.e5
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2910201788
Cited by
156
References
35
Citations by year
2026: 14 · 2025: 13 · 2024: 22 · 2023: 20 · 2022: 26 · 2021: 28 · 2020: 27 · 2019: 6
FWCI
7.28
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Japan Science and Technology Agency (JPMJPR13MC)
  • CREST
  • AMED (JP17gm0810003)
  • Japan Society for the Promotion of Science
  • 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
  • Chugai Pharmaceutical
  • AYUMI Pharmaceutical Corporation
  • Noevir Co., Ltd
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Medicinal Plant Pharmacodynamics Research
Keywords
semaphorin 3A, osteocytes, estrogen, bone aging, menopause, osteoporosis, bone homeostasis, osteocyte survival, neuropilin-1, ovariectomy, bone loss
MeSH terms
Aging, Animals, Bone Resorption, Estrogens, Female, Humans, Menopause, Mice, Inbred C57BL, Middle Aged, Osteocytes, Osteogenesis, Neuropilin-1, Semaphorin-3A, Mice, HEK293 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review