Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis.

By Chen Zhao, N. Irie, Y. Takada, K. Shimoda, T. Miyamoto, T. Nishiwaki, T. Suda, K. Matsuo. Cell Metabolism, 2006

781 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/da58bbe4acda77a4d6e2428b2b965ed0561eea1b

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In Cellular and Molecular Neuroscience

1. T. Martin
2. N. Sims
3. E. Pasquale

In Molecular Biology

1. S. Khosla
2. D. Monroe
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Citations in the corpus

• Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015, background): “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].”
• Eph-ephrin bidirectional signaling in physiology and disease. (2008, background): “Besides these developmental roles, EphB-ephrin-B bidirectional signaling between osteoblasts and osteoclasts has been implicated in the regulation of bone homeostasis in the adult (Zhao et al., 2006).”
• Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. (2014, background): “Interestingly, in that same work, ephrinB2/EphB4 receptor blockade resulted in enhanced osteoclast formation in vivo and in vitro, most likely at least partly due to interruption of the ephrinB2 reverse signaling in osteoclast progenitors, which inhibits osteoclast differentiation as proposed by Zha”
• Osteoblast-Osteoclast Communication and Bone Homeostasis (2020, background): “Similarly, overexpression of EPHB4 in osteoblasts increases bone mass in a transgenic mouse model [26].”
• Denosumab and bisphosphonates: different mechanisms of action and effects. (2011, background): “In addition, bidirectional signaling takes place in osteoclasts via the transmembrane ephrinB2 ligand and in osteoblasts by EphB4, the tyrosine kinase receptor of ephrinB2 [34,35].”
• Cellular mechanisms of bone remodeling (2010, background): “Other system involved in coupling of bone resorption to bone formation are the transmembrane proteins, ephrinB2, which are expressed on osteoblasts and EPH receptor B4 (EphB4), which are expressed on osteoclasts [32].”
• Estrogen and the Skeleton (2012, positive): “Binding of ephrinB2 to EphB4 leads to a suppression of osteoclastic activity and enhances osteoblastic differentiation (17); however, further studies are needed to define the extent to which ephrinB2-EphB4 signaling in osteoblastic cells results in the coupling of bone formation to bone resorption.”