Ephrins stimulate developmental bone growth

Abstract

The Eph receptor tyrosine kinases and their ligands, the ephrins, control boundary formation during cranial suture development. They also regulate mineral homeostasis in the long bones. We hypothesized that ephrins regulate bone growth in the calvarium separate from pattern formation, and that exogenous activation of Eph signaling can be used to promote bone synthesis. We found strong expression of beta‐galactosidase in the periosteum and the dura mater of late embryonic ephrin‐B2/LacZ and EphB2/LacZ mice (in which a lacZ reporter gene was knocked in to the ephrin‐B2 or EphB2 locus, respectively) after suture patterning was complete, but during the period of vigorous bone growth. EphB2 was particularly concentrated in the osteogenic fronts of the frontal bones. Treatment of e17.5 mouse calvariae for five days with recombinant ephrin‐B2 ectodomain fused to human Fc dramatically increased bone volume without changing bone density or interfrontal/sagittal suture widths. We conclude that Eph signaling stimulates bone synthesis apart from its role in cranial patterning. Thus, recombinant ephrin may be useful for the repair of cranial defects. Ongoing studies are concentrating on the mechanism of ephrin action in osteoblast differentiation and gene expression.