Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures

Targeted disruption of core binding factor alpha1 (Cbfa1) showed that Cbfa1 is an essential transcription factor in osteoblast differentiation and bon e formation. Furthermore, both in vitro and in vivo studies showed that Cbf a1 plays important roles in matrix production and mineralization. However, it remains to be clarified how Cbfa1 controls osteoblast differentiation, b one formation, and bone remodelling. To understand fully the physiological functions of Cbfa1, we generated transgenic mice that overexpressed Cbfa1 i n osteoblasts using type I collagen promoter. Unexpectedly, Cbfa1 transgeni c mice showed osteopenia with multiple fractures. Cortical bone, which was thin, porous, and enriched with osteopontin, was invaded by osteoclasts, de spite the absence of acceleration of osteoclastogenesis. Although the numbe r of neonatal osteoblasts was increased, their function was impaired in mat rix production and mineralization. Furthermore, terminally differentiated o steoblasts, which strongly express osteocalcin, and osteocytes were diminis hed greatly, whereas less mature osteoblasts expressing osteopontin accumul ated in adult bone. These data indicate that immature organization of corti cal bone, which was caused by the maturational blockage of osteoblasts, led to osteopenia and fragility in transgenic mice, demonstrating that Cbfa1 i nhibits osteoblast differentiation at a late stage.