BoneKEy Reports | BoneKEy Watch

EphrinB2/EphB4 signaling can enhance and inhibit osteoclastogenesis



DOI:10.1038/bonekey.2013.29

Signaling between EphB4, a tyrosine kinase receptor, and ephrinB2, its primary ligand, is thought to mediate bone formation and resorption through effects on osteoblasts and osteoclasts.

In the first study to characterize this interaction further, Arthur et al. investigated how EphB4 affects bone repair in a mouse model of traumatic injury. Col1-EphB4 transgenic mouse overexpressing EphB4 were compared with wild-type mice for differences in the bone healing process that occurred within 12 weeks of an induced femoral fracture. The repaired bones of Col1-EphB4 mice were stronger and stiffer than the controls, and a significant difference between tissue and bone volume was apparent within two weeks of the fracture. The callus of the transgenic mice showed increased mineral formation and chondrogenesis. Col1-EphB4 mice had fewer tartrate-resistant acid phosphatase-positive multinucleated osteoclasts, however, suggesting that EphB4 enhances endochondral ossification but inhibits the differentiation of osteoclasts during fracture repair.

In a second study, Takyar et al. used soluble EphB4 (sEphB4) as a tool in vitro and in vivo to investigate how ephrinB2/EphB4 signaling impacts on osteoclast and osteoblast differentiation. In vitro, sEphB4 inhibited phosphorylation of both molecules when introduced to cultures of osteoblasts, reducing expression of osteocalcin, dentin matrix protein-1, sclerostin and other late markers of osteoblast/osteoclast differentiation, but it increased the level of RANKL significantly.

In vivo, expression of early osteoblast markers such as Runx2, alkaline phosphatase and parathyroid hormone (PTH) receptor 1 reduced after treatment with sEphB4, irrespective of whether PTH was present. In contrast, treatment did not alter the bone formation rate or change the expression of late markers of osteocyte or osteoblast differentiation. When PTH was present, sEphB4 increased the formation of osteoclasts so much that the anabolic effect of PTH was canceled out, resulting in a decrease in trabecular number. In vitro, the same effect was seen only when osteoblasts were present, suggesting that the later stages of osteoblast differentiation are dependent on ephrinB2/EphB4 signaling.

Editor’s comment: Two studies that elucidate the role of ephrinB2/EphB4 signaling in osteoclastogenesis: Takyar et al. demonstrate that ephrinB2/EphB4 suppresses the anabolic response to PTH while enhancing osteoclastogenesis via RANKL, while Arthur et al. show that EphB4 overexpression in osteoblasts enhances fracture repair while inhibiting osteoclastogenesis. Thus, ephrinB2/EphB4 signaling emerges as a novel therapeutic target for enhancing the anabolic effect of PTH and for promoting fracture repair.


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