Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis

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.

Cell–cell signaling via Eph receptors and ephrins

“…A recent study also shows that B-class Ephs and ephrins mediate the activities of osteoclasts, which degrade bone, and osteoblasts, which form bone, to maintain bone homeostasis [19]. Indeed the osteoclasts express ephrin-B2, while osteoblasts express the corresponding EphB4 receptor.…”

“…Indeed the osteoclasts express ephrin-B2, while osteoblasts express the corresponding EphB4 receptor. Reverse signaling through ephrin-B2 into osteoclast precursors suppresses osteoclast differentiation, while forward signaling through EphB4 into osteoblasts enhances it -thereby maintaining bone homeostasis [19].…”

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…Recently, a system composed of the ephrin ligands and their specific receptors Eph has been described for its ability to control bone remodelling [80]. Two subclasses of Eph receptors have been defined according to their preferred ligand specificity, namely type A receptors (EphA) which bind to ephrins A, and type B receptors (EphB) which bind to ephrins B.…”

“…1). In this particular situation, signalling through EphB receptors is considered forward and, through ephrin B ligands, reverse signalling [80]. Interestingly, it was recently demonstrated that ephrin B2, mainly expressed by osteoclasts, and its specific receptor EphB4, expressed by osteoblasts, are involved in the control of bone homeostasis in which the EphB4 forward signalling favours an osteoblast differentiation process, whereas the reverse signalling through ephrin B2 ligands leads to an inhibitory effect on the osteoclast function.…”

“…Interestingly, it was recently demonstrated that ephrin B2, mainly expressed by osteoclasts, and its specific receptor EphB4, expressed by osteoblasts, are involved in the control of bone homeostasis in which the EphB4 forward signalling favours an osteoblast differentiation process, whereas the reverse signalling through ephrin B2 ligands leads to an inhibitory effect on the osteoclast function. The overall outcome of such an interaction favours bone formation [80].…”