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, Oct 05, 2015
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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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    ABSTRACT: We have previously shown that PTP-oc is an enhancer of the functional activity of osteoclasts and that EphA4 is a suppressor. Here, we provide evidence that PTP-oc enhances osteoclast activity in part through inactivation of EphA4 by dephosphorylating key phosphotyrosine (pY) residues of EphA4. We show that EphA4 was pulled down by the PTP-oc trapping mutant but not by the wild-type (WT) PTP-oc and that transgenic overexpression of PTP-oc in osteoclasts drastically decreased pY602 and pY779 residues of EphA4. Consistent with the previous findings that EphA4 deficiency increased pY173-Vav3 level [Rac-GTP exchange factor (GEF)] and enhanced bone resorption activity of osteoclasts, reintroduction of WT-Epha4 in Epha4 null osteoclasts led to ∼50% reduction in the pY173-Vav3 level and ∼2-fold increase in bone resorption activity. Overexpression of Y779F-Epha4 mutant in WT osteoclasts markedly increased in pY173-Vav3 and reduced bone resorption activity, but overexpression of Y602F-Epha4 mutant had no effect, suggesting that pY779 residue plays an important role in the EphA4-mediated suppression of osteoclast activity. Deficient EphA4 in osteoclasts has been shown to up-regulate Rac-GTPase and down-regulate Rho-GTPase. PTP-oc overexpression in osteoclasts also increased the GTP-Rac level to 300% of controls, but decreased the GTP-Rho level to ∼50% of controls. PTP-oc overexpression or deficient Epha4 each also reduced pY87-Ephexin level, which is a Rho GEF. Thus, PTP-oc may differentially regulate Rac signaling vs. Rho signaling through dephosphorylation of EphA4, which has shown to have opposing effects on Rac-GTPase vs. Rho-GTPase through differential regulation of Vav3 vs. Ephexin. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Biochemistry 02/2015; 116(8). DOI:10.1002/jcb.25137 · 3.26 Impact Factor
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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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    ABSTRACT: Bone marrow (BM) contains hematopoietic stem cells (HSCs) and nonhematopoietic cells. HSCs give rise to all types of mature blood cells, while the nonhematopoietic component includes osteoblasts/osteoclasts, endothelial cells (ECs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). These cells form specialized "niches" which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche", rich in blood vessels where ECs and mural cells (pericytes and smooth muscle cells), create a microenvironment affecting the behavior of several stem and progenitor cells. The vessel wall acts as an independent niche for the recruitment of EPCs and MSCs. This chapter will focus on the description of the role of BM niches in the control of angiogenesis occurring during multiple myeloma progression. Copyright © 2015 Elsevier Inc. All rights reserved.
    International review of cell and molecular biology 01/2015; 314:259-82. DOI:10.1016/bs.ircmb.2014.10.004 · 3.42 Impact Factor
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    • "Recently, semaphorins have been targeted as new molecules directly implicated in cell-cell communication pathways that occur between osteoclasts and osteoblasts (Delorme et al., 2005; Takegahara et al., 2006; Zhao et al., 2006; Sutton et al., 2008; Irie et al., 2009; Leah, 2011; Negishi-Koga et al., 2011; Hayashi et al., 2012; Fukuda et al., 2013; Ohlsson, 2013). Originally depicted as axon-guidance molecules, recent studies have demonstrated their involvement outside of the nervous system, where they play key roles in cell migration, tissue development, and angiogenesis (Tamagnone and Comoglio, 2000; Dickson, 2002; Huber et al., 2003; Tran et al., 2007; Suzuki et al., 2008; Larrivee et al., 2009). "
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    ABSTRACT: Semaphorin 4d (Sema4d) has been proposed as a novel target gene for the treatment of osteoporosis. Recently, we fabricated a site-specific bone-targeting system from polymeric nanoparticles that demonstrates an ability to prevent bone loss in an osteoporotic model by interfering with Sema4d gene expression using small interference RNA (siRNA) molecules. The aim of the present investigation was to determine the effects of this targeting system on the periodontium, an area of high bone turnover. We demonstrated, by single photon emission computed tomography, that intravenous injection of this molecule in ovariectomized Balb/C mice is able to target alveolar bone peaking 4 hr post-injection. We then compared, by histological analysis, the bone volume/total volume (BV/TV), alveolar bone height loss, immunohistochemical expression of Sema4d, and total number of osteoclasts in mandibular alveolar bone. Four treatment modalities were compared as follows: (1) sham-operated, (2) OVX-operated, (3) OVX+estrogen replacement therapy, and (4) OVX+siRNA-Sema4d animals. The results from the present study demonstrate that an osteoporotic condition significantly increases alveolar bone height loss, and that the therapeutic effects via bone-targeting systems featuring interference of Sema4d are able to partly counteract alveolar bone loss caused by osteoporosis. While the future therapeutic demand for the large number of patients suffering from osteoporosis faces many challenges, we demonstrate within the present study an effective drug-delivery moiety with anabolic effects on the bone remodeling cycle able to locate and target alveolar bone regeneration.
    Journal of Dental Research 09/2014; 93(11). DOI:10.1177/0022034514552676 · 4.14 Impact Factor
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