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Cited by 777Bone Metabolism and DiseasesAxon Guidance and Neuronal SignalingMedicinal Plant Pharmacodynamics Research

Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis

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Zhao, Chen, Irie, Naoko, Takada, Yasunari, Shimoda, Kouji, Miyamoto, Takeshi, Nishiwaki, Toru, Suda, Toshio, Matsuo, Koichi·2006·Cell Metabolism
DOI 10.1016/j.cmet.2006.05.012
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Abstract

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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Crossref · 10.1016/j.cmet.2006.05.012

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  • EphrinB2/ephrinB4 binding transduces bidirectional signals that promote osteoblast differentiation, while reverse signaling inhibits osteoclastogenesis.

    “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]

  • EphrinB2/ephrinB4 pathway may be involved in ending bone resorption and inducing osteoblast differentiation in the transition phase.

    “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]

  • EphrinB2 is a membrane-bound molecule expressed in mature osteoclasts that binds to ephrinB4 in the plasma membrane of osteoblasts.

    “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]

  • The communication route between osteoclasts and osteoblasts involves a bidirectional signaling pathway mediated by EphrinB2-EphB4 that links suppression of osteoclastogenesis to osteogenesis within each BMU.

    “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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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
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2006-08
Volume
4
Issue
2
Pages
111-121
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2006.05.012
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
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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