Cbfa1: a molecular switch in osteoblast biology.

During the past 4 years, our molecular understanding of osteoblast biology has made rapid progress due to the characterization of the function of one molecule, Cbfa1. This member of the runt/Cbfa family of transcription factors was first identified as the nuclear protein binding to an osteoblast-specific cis-acting element activating the expression of Osteocalcin, the most osteoblast-specific gene. Cbfa1 was then shown to regulate the expression of all the major genes expressed by osteoblasts. Consistent with this ability, genetic experiments identified Cbfa1 as a key regulator of osteoblast differentiation in vivo. Indeed, analysis of Cbfa1-deficient mice revealed that osteoblast differentiation is arrested in absence of Cbfa1, demonstrating both that it is required for this process and that no parallel pathway can overcome its absence. The importance of Cbfa1 in controlling osteoblast differentiation was further emphasized by the identification of Cbfa1 haploinsufficiency as the cause of cleidocranial dysplasia in humans and mice, a syndrome characterized by generalized bone defects. Lastly, Cbfa1 was shown to have a role beyond development and differentiation, regulating the rate of bone matrix deposition by differentiated osteoblasts. Thus, Cbfa1 is a critical gene not only for osteoblast differentiation but also for osteoblast function. These aspects, as well as the more recent progresses in understanding Cbfa1 biology, are the focuses of this review.