Bidirectional EphrinB2-EphB4 Signaling Controls Bone Homeostasis

Department of Microbiology and Immunology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan.
Cell Metabolism (Impact Factor: 17.57). 09/2006; 4(2):111-21. DOI: 10.1016/j.cmet.2006.05.012
Source: PubMed


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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Available from: Koichi Matsuo
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    • "The Eph-mediated signal is known as the forward signaling and the Efn-mediated signal in neighboring cells is called the reverse signaling. Of all the members of Ephs, mature osteoclasts express predominantly EphA4 [Zhao et al., 2006; Irie et al., 2009; Stiffel et al., 2014]. "
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    • "Osteoblasts differentiation and function are coupled to osteoclastogenesis by means of Ephrin/Eph pathway. Stimulation of the receptor Eph4 on osteoblasts through Ephrin B2 expressed by osteoclasts promotes osteoblastogenesis, while reverse signaling through Ephrin B2 inhibits osteoclast differentiation (Zhao et al., 2006). Osteoblasts produce a variety of hematopoietic growth factors, including receptor activator of NF-kappa ligand (RANKL) and macrophage-CSF (Yasuda et al., 1998). "
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