Abstract
To test if ephrin B1 overexpression enhances bone mass, we generated transgenic mice overexpressing ephrin B1 under the control of a 3.6 kb rat collagen 1A1 promoter (Col3.6-Tgefnb1). Col3.6-Tgefnb1 mice express 6-, 12- and 14-fold greater levels of full-length ephrin B1 protein in bone marrow stromal cells, calvarial osteoblasts, and osteoclasts, respectively. The long bones of both genders of Col3.6-Tgefnb1 mice have increased trabecular bone volume, trabecular number, and trabecular thickness and decreased trabecular separation. Enhanced bone formation and decreased bone resorption contributed to this increase in trabecular bone mass in Col3.6-Tgefnb1 mice. Consistent with these findings, our in vitro studies showed that overexpression of ephrin B1 increased osteoblast differentiation and mineralization, osterix and collagen 1A1 expression in bone marrow stromal cells. Interaction of ephrin B1 with soluble clustered EphB2-Fc decreased osteoclast precursor differentiation into multinucleated cells. Furthermore, we demonstrated that the mechanical loading-induced increase in EphB2 expression and newly formed bone were significantly greater in the Col3.6-Tgefnb1 mice than in WT littermate controls. Our findings that overexpression of ephrin B1 in bone cells enhances bone mass and promotes a skeletal anabolic response to mechanical loading suggest that manipulation of ephrin B1 actions in bone may provide a means to sensitize the skeleton to mechanical strain to stimulate new bone formation.
Highlights
Osteoporosis is a common disease characterized by an agedependent decrease in bone mineral density (BMD) and a microarchitectural deterioration of bone tissue with a consequent increase in the risk of developing fragility fractures of the hip, spine, and other skeletal sites [1]
We found that osteoblasts and bone marrow stromal (BMS) cells expressed both ephrin B1 ligand and EphB2 receptor and that interaction of ephrin B1 with EphB2 led to osteoblast differentiation and bone formation [5]
Our findings suggest that manipulation of ephrin B1 actions in bone may provide a means to sensitize the skeleton to mechanical strain to stimulate new bone formation
Summary
Osteoporosis is a common disease characterized by an agedependent decrease in bone mineral density (BMD) and a microarchitectural deterioration of bone tissue with a consequent increase in the risk of developing fragility fractures of the hip, spine, and other skeletal sites [1]. Studies on key regulatory molecules and their signaling pathways that control formation and activity of osteoblasts are essential to developing therapeutic strategies to identify novel anabolic therapies In this regard, ephrin ligands and their receptors have been shown to play key roles in the growth and development of multiple tissues including the skeleton [2,3,4,5]. Benson et al demonstrated that ephrin B2 was upregulated at the sites of bone injury, and ephrin B2 stimulated forward signaling participated in fracture repair [9] These experimental and genetic studies strongly suggested that ephrin B1/2 mediated reverse signaling via its cytoplasmic tail as well as its receptor-mediated forward signaling were essential in craniofacial development, bone formation and regeneration processes
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