Parathyroid Hormone Controls Receptor Activator of NF-κB Ligand Gene Expression via a Distant Transcriptional Enhancer

摘要: RANKL, a protein essential for osteoclast development and survival, is stimulated by parathyroid hormone (PTH) via PTH receptor 1/cyclic AMP (cAMP)/protein kinase A (PKA)/CREB cascade, exclusively in osteoblastic cells. We report that bacterial artificial chromosome-based transcriptional reporter construct containing 120 kb of RANKL 5-flanking region was dibutyryl-cAMP stromal/osteoblastic cells, but not other cell types. Full cAMP responsiveness dependent upon conserved 715-bp located 76 upstream from the transcription start site, which we identified sequential deletion analysis comparison human mouse genomic sequences silico. This contained consensus bound CREB osteoblast-specific factor Runx2, when mutated blunted responsiveness. Overexpression Runx2 potentiated endogenous gene cell-type-specific manner. Lastly, abrogated mice deleted this region. Thus, determined distant regulatory responds to manner may contribute such cell-type specificity. Calcium homeostasis life terrestrial vertebrates, has evolved as principle responsible maintaining extracellular levels calcium within physiologic range (57). When