Suppression of bone formation by osteoclastic expression of semaphorin 4D
Abstract
Most of the currently available drugs for osteoporosis inhibit osteoclastic bone resorption; only a few drugs promote osteoblastic bone formation. It is thus becoming increasingly necessary to identify the factors that regulate bone formation. We found that osteoclasts express semaphorin 4D (Sema4D), previously shown to be an axon guidance molecule, which potently inhibits bone formation. The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. Sema4d-/- mice, Plxnb1-/- mice and mice expressing a dominant-negative RhoA specifically in osteoblasts showed an osteosclerotic phenotype due to augmented bone formation. Notably, Sema4D-specific antibody treatment markedly prevented bone loss in a model of postmenopausal osteoporosis. Thus, Sema4D has emerged as a new therapeutic target for the discovery and development of bone-increasing drugs.
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Plexin-B1 has important roles in immune system activation and bone homeostasis in adult physiology.
“However Plexin-B1 has importance roles in immune system activation and bone homeostasis in adult physiology23–25”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [25]
Osteoclasts suppress bone formation by expressing Sema4D.
“Sema4D expressed in osteoclasts binds to its receptor (Plexin-B1) present in osteoblasts and inhibits IGF-1 pathway, essential for osteoblast differentiation [172], suggesting that osteoclasts suppress bone formation by expressing Sema4D.”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [172]
Semaphorins are a large family of glycoproteins, membrane-bound and soluble, found in a wide range of tissues, involved in immune response, organogenesis, cardiovascular development, and tumor progression.
“Semaphorins comprise a large family of glycoproteins which are not only membrane-bound but also exist as soluble forms that are found in a wide range of tissues and shown to be involved in diverse biological processes such as immune response, organogenesis, cardiovascular development, and tumor progression [172, 173].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [172]
Sema4D expressed in osteoclasts binds to Plexin-B1 on osteoblasts and inhibits IGF-1 pathway essential for osteoblast differentiation.
“Sema4D expressed in osteoclasts binds to its receptor (Plexin-B1) present in osteoblasts and inhibits IGF-1 pathway, essential for osteoblast differentiation [172], suggesting that osteoclasts suppress bone formation by expressing Sema4D.”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [172]
Osteoclasts express Sema4D, which inhibits bone formation during bone resorption.
“The osteoclasts express a factor called semaphorin4D (Sema4D) that inhibits bone formation during bone resorption [172].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [172]
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- Authors
- Negishi-Koga, T., Shinohara, M., Komatsu, N., Bito, H., Kodama, T., Friedel, R. H., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- The University of Tokyo (JP)
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Takayanagi, Hiroshi
- Venue
- Nature Medicine
- Published
- 2011-10-23
- Volume
- 17
- Issue
- 11
- Pages
- 1473-1480
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2157222066
- Cited by
- 498
- References
- 55
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 26 · 2023: 28 · 2022: 39 · 2021: 36 · 2020: 44 · 2019: 36 · 2018: 36 · 2017: 30 · 2016: 40 · 2015: 39 · 2014: 40 · 2013: 29 · 2012: 26
- FWCI
- 13.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22689048, 20670002, 23659149)
- 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
- Sema4D, osteoclasts, osteogenic differentiation, bone formation, osteoporosis, postmenopausal osteoporosis, Plexin-B1, RhoA, IGF-1 signaling, osteosclerosis, bone loss
- MeSH terms
- Animals, Antibodies, Bone Resorption, Cell Differentiation, Cell Movement, Cells, Cultured, Female, Femur, Humans, Mice, Inbred C57BL, Nerve Tissue Proteins, Osteoclasts, Osteogenesis, Osteoporosis, Receptors, Cell Surface, Signal Transduction, Antigens, CD, Mice, Knockout, rhoA GTP-Binding Protein, Semaphorins, Mice
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 ›
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