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The ephrin-B family of membrane-bound ligands is involved in skeletal patterning, osteogenesis, and bone homeostasis. Yet, despite the increasing collection of data affirming their importance in bone, the Eph tyrosine kinases that serve as the receptors for these ephrins in osteoblast stem cell niches remain unidentified. Here we report the expression of EphB3 at sites of bone growth in the embryo, especially at the calvaria suture fronts, periosteum, chondrocytes, and trabeculae of developing long bones. Strong EphB3 expression persisted in the adult calvarial sutures and in the proliferative chondrocytes of long bones, both of which are documented niches for osteoblastic stem cells. We observed EphB3-positive cells in the tissue filling a created calvarial injury, further implying EphB3 involvement in bone healing. Genetic knockout of EphB3 caused an increase in the bone tissue volume as a fraction of total volume in 6-week-old calvaria and in femoral trabecular density, compared to wild type controls. This difference resolved by 12 weeks of age, when we instead observed an increase in the bone volume of femoral trabeculae and in trabecular thickness. Our data identify EphB3 as a candidate regulator of osteogenesis either alone or in combination with other bone-expressed Ephs, and indicate that it appears to function as a limiter of bone growth. [ABSTRACT FROM AUTHOR]