ERRalpha regulates osteoblastic and adipogenic differentiation of mouse bone marrow mesenchymal stem cells

The orphan nuclear receptor estrogen-related receptor-alpha (ERRalpha) has been reported to have both a positive and a negative regulatory role in osteoblastic and adipocytic differentiation. We have studied the role of ERRalpha in osteoblastic and adipogenic differentiation of mesenchymal stem cells. Bone marrow mesenchymal stem cells were isolated from ERRalpha deficient mice and their differentiation capacities were compared to that of the wild-type cells. ERRalpha deficient cultures displayed reduced cellular proliferation, osteoblastic differentiation, and mineralization. In the complementary experiment, overexpression of ERRalpha in MC3T3-E1 cells increased the expression of osteoblastic markers and mineralization. Alterations in the expression of bone sialoprotein (BSP) may at least partially explain the effects on mineralization as BSP expression was reduced in ERRalpha deficient MSCs and enhanced upon ERRalpha overexpression in MC3T3-E1 cells. Furthermore, a luciferase reporter construct driven by the BSP promoter was efficiently transactivated by ERRalpha. Under adipogenic conditions, ERRalpha deficient cultures displayed reduced adipocytic differentiation. Our data thus propose a positive role for ERRalpha in osteoblastic and adipocytic differentiation. The variability in the results yielded in the different studies implies that ERRalpha may play different roles in bone under different physiological conditions.