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

The nuclear orphan receptor human estrogen receptor-related receptor (ERR)-α is implicated in bone metabolism. We studied the effect of ERRα silencing in human mesenchymal stem cells (hMSCs) during osteoblastogenesis. We found that ERRα 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 ERRα inhibited adipogenesis, resulting in a decrease in adipocyte number and adipocyte marker gene expression. In line with a negative role of ERRα in bone metabolism, we found that adult female and male ERRα-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, ERRα-deficient osteoblasts displayed increased differentiation properties in vitro in line with our observations in hMSCs. In summary, we ident...