| dc.description.abstract | Skeletal growth deficiencies arising from birth defects, injury or disease exist despite advances in therapy; as a public health imperative, this reflects the need for a deeper understanding of its causes. The molecular mechanisms underlying bone growth are complex, however, the exact mechanism remains unclear. It is well known that the craniofacial skeleton forms from the neural crest, with the parietal bones forming from paraxial mesoderm. The cranial vault consists of the frontal and paired parietal bones, and interposed between them are sutures that, together with the periosteum, serve as active sites of osteogenesis during skull growth and repair. Interactions between the cranial sutures and periosteum are complex and involve a network of signaling pathways that determine mesenchymal lineage fate specification. Ephrins and their Eph-kinases constitute a unique signaling system in calvarial growth and morphogenesis, and mutations in genes encoding these proteins frequently result in craniosynostosis. First reported in 1987, Eph kinases total 14 and their ligands or ‘ephrins’ total 8 in the mammalian vertebrate. Of interest to us are the transmembrane B-ephrins that mediate diverse cell-cell contact-dependent events such as cell migration, tissue boundary formation during osteogenesis and axon guidance through ‘forward’ signaling into Eph-kinases; ephrins also act as ‘receptors’ to which Eph-kinases bind in a process termed ‘reverse’ signaling. Ephrin-B1 is crucial in mouse development, as its ablation causes skeletal defects arising from defective migration of neural crest and mesenchymal precursors, findings consistent with human CFN syndrome caused by mutations in ephrin-B1. This ligand is also critical in BMSC differentiation into osteoblasts via upregulation of Osterix. Ephrin-B2 forward signaling promotes osteoblast differentiation and, via hormone-mediated effects, promotes OB maturation and bone formation through ephrin-B2 upregulation in OBs themselves. We observed ephrin-B2 in the cranial sutures/ periosteum and its upregulation at sites of injury to the adult parietal calvaria; further, recombinant ephrin-B2 dramatically increased bone mass in embryonic calvaria, implying anabolic roles for this ligand in bone. Moreover, in the developing embryonic calvaria, the combined ablation of ephrin-B1/B2 in Axin2 suture stem cell niche dramatically impaired calvarial bone growth suggesting that these ephrins work together in regulating the niche. | en |
