PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner.

Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis, and increases zinc finger protein 467 () expression. In contrast, genetic loss of increased expression and shifts mesenchymal progenitor cell fate toward osteogenesis and higher bone mass. PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of in osteogenic precursors would lead to high bone mass in mice. but not mice exhibit high bone mass and greater osteogenic differentiation similar to the mice. qPCR results revealed that PTH suppressed expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of and gene silencing of caused an increase in mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of resulted in higher nuclear translocation of NFκB1 that binds to the P2 promoter of the and increased its transcription. As expected, cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in COBs, and the pro-osteogenic effect of deletion was blocked by gene silencing of or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of results in a pathway that increases transcription via NFκB1 and thus cellular responsiveness to PTH/PTHrP, ultimately leading to enhanced bone formation.