Abstract
The orphan nuclear estrogen receptor-related receptor a (ERRa), is expressed by many cell types, but is very highly expressed by osteoblastic cells in which it transactivates at least one osteoblast-associated gene, osteopontin. To study the putative involvement of ERRa in bone, we first assessed its expression in rat calvaria (RC) in vivo and in RC cells in vitro. ERRa mRNA and protein were expressed at all developmental stages from early osteoprogenitors to bone-forming osteoblasts, but protein was most abundant in mature cuboidal osteoblasts. To assess a functional role for ERRa in osteoblast differentiation and bone formation , we blocked its expression by antisense oligonucle-otides in either proliferating or differentiating RC cell cultures and found inhibition of cell growth and a proliferation independent inhibition of differentiation. On the other hand, ERRa overexpression in RC cells increased differentiation and maturation of progenitors to mature bone-forming cells. Our findings show that ERRa is highly expressed throughout the osteoblast developmental sequence and plays a physiological role in differentiation and bone formation at both proliferation and differentiation stages. In addition, we found that manipulation of receptor levels in the absence of known ligand is a fruitful approach for functional analysis of this orphan receptor and identification of potential target genes.