In vitro and in vivo evidence for orphan nuclear receptor ROR alpha function in bone metabolism

Bone is a major target site for steroid hormone action. Steroid hormones li ke cortisol, vitamin D, and estradiol are responsible for principal events associated with bone formation and resorption. Over the past decade, new me mbers of the nuclear hormone gene family have been identified that lack kno wn ligands. These orphan receptors can be used to uncover signaling molecul es that regulate yet unidentified physiological networks. In the present st udy the function of retinoic acid receptor-related orphan receptor (ROR) al pha in bone metabolism has been examined. We showed that ROR alpha and ROR gamma, but not ROR beta, are expressed in mesenchymal stem cells derived fr om bone marrow. Interestingly, for ROR alpha We observed an increased messe nger signal expression between control cells and cells undergoing osteogeni c differentiation. Furthermore, the direct activation of mouse bone sialopr otein by ROR alpha, typically 7-fold, has been shown. In contrast, transien t overexpression of RORa! overrides the activation of the osteocalcin promo ter by 1 alpha,25-dihydroxyvitamin D-3. In addition, we have investigated b one mass parameters and bone geometry in the mouse mutant staggerer (sg/sg) , a mouse strain that carries a deletion within the ROR alpha gene. Homozyg ote mutants have thin long bones compared with the heterozygote animals and wild-type littermates. More interestingly, the bones of the sg/sg animals are osteopenic as indicated by the comparison of bone mineral contents of s g/sg animals to the heterozygote and wild-type animals. We conclude that th ese in vitro and in vivo results suggest a function for ROR alpha in bone b iology. ROR alpha most likely acts by direct modulation of a bone matrix co mponent.