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Absence of Estrogen Receptor-Related- Increases Osteoblastic Differentiation and Cancellous Bone Mineral Density

Musculoskeletal Disease Area (I.D., S.G., F.M., L.W., G.E., A.S., M.K., B.F.), Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland; and Cardiovascular and Metabolism Disease Area (S.R.), Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139

Address all correspondence and requests for reprints to: Dr. B. Fournier, Novartis Institutes for Biomedical Research, Musculoskeletal Diseases, WKL-125.9.17, 4002 Basel, Switzerland. E-mail: brigitte.fournier{at}novartis.com.

The nuclear orphan receptor human estrogen receptor-related receptor (ERR)- is implicated in bone metabolism. We studied the effect of ERR silencing in human mesenchymal stem cells (hMSCs) during osteoblastogenesis. We found that ERR silencing led to an increase of bone sialoprotein and a decrease of osteopontin mRNA levels, suggesting enhanced osteoblastic differentiation. This was confirmed by an increased ability of hMSCs to deposit calcium. Concomitantly, knockdown of ERR inhibited adipogenesis, resulting in a decrease in adipocyte number and adipocyte marker gene expression. In line with a negative role of ERR in bone metabolism, we found that adult female and male ERR-deficient mice displayed a moderate increase in femoral cancellous bone volume and density. Osteoblast surface was increased and marrow fat volume decreased in these animals. Furthermore, ERR-deficient osteoblasts displayed increased differentiation properties in vitro in line with our observations in hMSCs. In summary, we identified a role for ERR in bone mass regulation by affecting osteoblastic differentiation.