Absence of ERRα in Female Mice Confers Resistance to Bone Loss Induced by Age or Estrogen-Deficiency

Background: ERR alpha is an orphan member of the nuclear hormone receptor superfamily, which acts as a transcription factor and is involved in various metabolic processes. ERR alpha is also highly expressed in ossification zones during mouse development as well as in human bones and cell lines. Previous data have shown that this receptor up-modulates the expression of osteopontin, which acts as an inhibitor of bone mineralization and whose absence results in resistance to ovariectomy-induced bone loss. Altogether this suggests that ERR alpha may negatively regulate bone mass and could impact on bone fragility that occurs in the absence of estrogens. Methods/Principal Findings: In this report, we have determined the in vivo effect of ERR alpha on bone, using knock-out mice. Relative to wild type animals, female ERR alpha KO bones do not age and are resistant to bone loss induced by estrogen-withdrawal. Strikingly male ERR alpha KO mice are indistinguishable from their wild type counterparts, both at the unchallenged or gonadectomized state. Using primary cell cultures originating from ERR alpha KO bone marrow, we also show that ERR alpha acts as an inhibitor of osteoblast differentiation. Conclusion/Significance: Down-regulating ERR alpha could thus be beneficial against osteoporosis.