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Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis
Open accessAbstract
Bone homeostasis requires a delicate balance between the activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Various molecules coordinate osteoclast function with that of osteoblasts; however, molecules that mediate osteoclast-osteoblast interactions by simultaneous signal transduction in both cell types have not yet been identified. Here we show that osteoclasts express the NFATc1 target gene Efnb2 (encoding ephrinB2), while osteoblasts express the receptor EphB4, along with other ephrin-Eph family members. Using gain- and loss-of-function experiments, we demonstrate that reverse signaling through ephrinB2 into osteoclast precursors suppresses osteoclast differentiation by inhibiting the osteoclastogenic c-Fos-NFATc1 cascade. In addition, forward signaling through EphB4 into osteoblasts enhances osteogenic differentiation, and overexpression of EphB4 in osteoblasts increases bone mass in transgenic mice. These data demonstrate that ephrin-Eph bidirectional signaling links two major molecular mechanisms for cell differentiation--one in osteoclasts and the other in osteoblasts--thereby maintaining bone homeostasis.
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“The ephrinB2/ephrinB4 binding transduces bidirectional signals, which promote osteoblast differentiation, whereas the reverse signaling (ephrinB4/ephrinB2) inhibits osteoclastogenesis [178] (Figure 5).”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [178]
In the citing paper
“These findings suggest that ephrinB2/ephrinB4 pathway may be involved in the ending of bone resorption and induces osteoblast differentiation in the transition phase [178].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [178]
In the citing paper
“One of these factors is ephrinB2, a membrane-bound molecule expressed in mature osteoclasts, which bind to ephrinB4, found in the plasma membrane of osteoblasts.”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [178]
In the citing paper
“The communication route between osteoclasts and osteoblasts involves a bidirectional signaling pathway mediated by EphrinB2‐EphB4 that links the suppression of osteoclastogenesis to osteogenesis within each BMU.251”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [251]
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Metadata
- Authors
- Zhao, C., Irie, N., Takada, Y., Shimoda, K., Miyamoto, T., Nishiwaki, T., Suda, T., & Matsuo, K.
- Affiliations
- Keio University (JP)
- Corresponding author
- Matsuo, Koichi
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 4
- Issue
- 2
- Pages
- 111-121
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2026387061
- Cited by
- 777
- References
- 56
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 23 · 2023: 34 · 2022: 35 · 2021: 45 · 2020: 49 · 2019: 33 · 2018: 42 · 2017: 42 · 2016: 47 · 2015: 39 · 2014: 46 · 2013: 40 · 2012: 59
- FWCI
- 15.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Medicinal Plant Pharmacodynamics Research
- Keywords
- ephrin-B2, EphB4, bidirectional signaling, bone homeostasis, osteoclastogenesis, osteogenic differentiation, osteoblast-osteoclast interaction, NFATc1, c-fos, bone mass, Eph/ephrin signaling
- MeSH terms
- Animals, Base Sequence, Bone and Bones, Cell Differentiation, Cells, Cultured, Homeostasis, Mice, Transgenic, Molecular Sequence Data, Osteoblasts, Osteoclasts, Signal Transduction, Up-Regulation, Proto-Oncogene Proteins c-fos, Receptor, EphB4, Ephrin-B2, NFATC Transcription Factors, Mice
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