EphrinB2 signaling in osteoblasts promotes bone mineralization by preventing apoptosis
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The Eph/ephrin family of receptor tyrosine kinases has the unique ability to signal both in forward (through the Eph receptor) and reverse (through the ephrin ligand) direction, yet the physiological role of ephrinB2 reverse signaling remains poorly understood. Within the cells that form bone (osteoblasts) ephrinB2 is the only family member whose production is regulated by parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP), two agents that stimulate bone formation. Pharmacological inhibition of the interaction of ephrinB2 with one of its receptors, EphB4, impairs osteoblast differentiation in vitro and in vivo. By studying mice with conditional deletion of ephrinB2 from osteoblasts, we examined the role of ephrinB2 on bone formation and the anabolic action of PTH . Osteoblasts from these mice demonstrated impaired differentiation and reduced support of osteoclastogenesis. In vivo this resulted in delayed osteoid mineralization, and impaired osteoblastic response to anabolic PTH treatment. Furthermore, mice with loss of ephrinB2 also exhibited profoundly higher osteoblast apoptosis compared to control mice, both in vivo and in vitro, mediated by activation of caspase-8. These findings indicate that ephrinB2 reverse signaling within the osteoblast lineage is required for PTH anabolic action and maintains osteoblast differentiation by limiting apoptosis.
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