Osteoprotection by semaphorin 3A
Abstract
The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine-based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/β-catenin signalling pathway. The osteopenic phenotype in Sema3a−/− mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases.
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Sema3A is found in osteoblasts and is considered an inhibitor of osteoclastogenesis.
“Conversely, another member of semaphorin family (Sema3A) has been found in osteoblasts and is considered an inhibitor of osteoclastogenesis [177].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [177]
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- Authors
- Hayashi, M., Nakashima, T., Taniguchi, M., Kodama, T., Kumanogoh, A., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Sapporo Medical University (JP)
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Corresponding author
- Takayanagi, Hiroshi
- Venue
- Nature
- Published
- 2012-04-18
- Volume
- 485
- Issue
- 7396
- Pages
- 69-74
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1976265795
- Cited by
- 606
- References
- 46
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 44 · 2023: 47 · 2022: 59 · 2021: 43 · 2020: 45 · 2019: 34 · 2018: 53 · 2017: 45 · 2016: 44 · 2015: 39 · 2014: 29 · 2013: 35 · 2012: 25
- FWCI
- 16.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (21590196)
- Exploratory Research for Advanced Technology
- 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, osteoprotection, osteoclastogenesis, osteogenic differentiation, bone resorption, bone formation, neuropilin-1, RANKL, ITAM, RhoA signaling, Wnt/β-catenin signaling, adipogenesis, bone regeneration, osteopenia, bone and joint diseases
- MeSH terms
- Animals, Bone Marrow Cells, Bone Resorption, Cell Differentiation, Cells, Cultured, Female, Male, Osteoblasts, Osteoclasts, Osteogenesis, Skull, Adipocytes, Coculture Techniques, Cytoprotection, Neuropilin-1, Semaphorin-3A, Mice, Wnt Signaling Pathway
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