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Published online 28 May 2001. doi:10.1083/jcb.153.5.971
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© The Rockefeller University Press, 0021-9525/2001//971 $5.00
The Journal of Cell Biology, Volume 153, Number 5, , 2001 971-984

Original Article

The Orphan Nuclear Estrogen Receptor–Related Receptor {alpha} (Err{alpha}) Is Expressed Throughout Osteoblast Differentiation and Regulates Bone Formation in Vitro



E. Bonnelyea, L. Merdada, V. Kunga, and J.E. Aubina

a Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
Department of Anatomy and Cell Biology, Faculty of Medicine, University of Toronto, Rm. 6255, Medical Sciences Bldg., 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.(416) 978-3954(416) 978-4220

jane.aubin{at}utoronto.ca

The orphan nuclear estrogen receptor–related receptor {alpha} (ERR{alpha}), 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 ERR{alpha} in bone, we first assessed its expression in rat calvaria (RC) in vivo and in RC cells in vitro. ERR{alpha} 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 ERR{alpha} in osteoblast differentiation and bone formation, we blocked its expression by antisense oligonucleotides 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, ERR{alpha} overexpression in RC cells increased differentiation and maturation of progenitors to mature bone-forming cells. Our findings show that ERR{alpha} 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.

Key Words: osteoblasts • bone • nuclear receptor • estrogen related • differentiation

© 2001 The Rockefeller University Press

Abbreviations used in this paper: ALP, alkaline phosphatase; ANOVA, analysis of variance; COLLI, collagen type I {alpha} chain; ER, estrogen receptor; ERR{alpha}, estrogen receptor–related receptor {alpha}; OCN, osteocalcin; OPN, osteopontin; RC, rat calvaria; RT, reverse transcription; UTR, untranslated region.


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