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

The nuclear orphan receptor human estrogen receptor-related receptor (ERR)-alpha is implicated in bone metabolism. We studied the effect of ERR alpha silencing in human mesenchymal stem cells (hMSCs) during osteoblastogenesis. We found that ERR alpha 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 alpha inhibited adipogenesis, resulting in a decrease in adipocyte number and adipocyte marker gene expression. In line with a negative role of ERR alpha in bone metabolism, we found that adult female and male ERR alpha-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 alpha-deficient osteoblasts displayed increased differentiation properties in vitro in line with our observations in hMSCs. In summary, we identified a role for ERR alpha in bone mass regulation by affecting osteoblastic differentiation. (Endocrinology 150: 4463-4472, 2009)