| First Author | Farr JN | Year | 2018 |
| Journal | J Bone Miner Res | Volume | 33 |
| Issue | 4 | Pages | 720-731 |
| PubMed ID | 29206307 | Mgi Jnum | J:315970 |
| Mgi Id | MGI:6831926 | Doi | 10.1002/jbmr.3351 |
| Citation | Farr JN, et al. (2018) Osteoprotection Through the Deletion of the Transcription Factor Rorbeta in Mice. J Bone Miner Res 33(4):720-731 |
| abstractText | There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor beta (Rorbeta) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorbeta is markedly increased in bone marrow-derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorbeta in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorbeta in osteoblasts enhances Wnt signaling, specifically through increased recruitment of beta-catenin to T-cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg. This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorbeta-deficient cells. Consistent with our in vitro data, genetic deletion of Rorbeta in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorbeta(-/-) mice was also associated with increased bone protein levels of TCF7 and OPG. These data demonstrate that loss of Rorbeta has beneficial skeletal effects by increasing bone formation and decreasing bone resorption, at least in part through beta-catenin-dependent activation of the Wnt pathway. Thus, inhibition of Rorbeta represents a novel approach to potentially prevent or reverse osteoporosis. (c) 2017 American Society for Bone and Mineral Research. |
