Receptor activator of NF-B ligand (RankL) is a potent osteoclastogenic cytokine whose expression is regulated at the transcriptional level by 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃), PKA activators such as PTH and gp130-activating cytokines such as oncostatin M (OSM). We recently identified five highly conserved chromatin domains located significant distances upstream of the RankL transcriptional start site (TSS) that contribute to the ability of 1,25-(OH)₂D₃ and its receptor to enhance RankL gene output. We therefore screened these five common regulatory regions for their potential ability to mediate the actions of PKA- and gp130-activators using a directed ChIP approach employing antibodies to the PKA target CREB and the gp130 target Stat3. CREB was identified at each of the upstream regulatory regions; Stat3, in contrast, was associated with only a subset. Interestingly, only the most distal of these regions demonstrated CREB- and OSM-regulated transcriptional activity in a heterologous transfection system. Mapping studies pointed to two highly conserved cAMP response elements as well as an adjacent regulatory site which bound Runx2 and was able to influence both basal as well as hormone-inducible RankL activity. Surprisingly, PKA and gp130 activation prompted recruitment of RNA polymerase II to the five distal enhancers as well as to the RankL TSS. Activation was also accompanied by a significant and location-selective rise in histone 4 acetylation. This study demonstrates that the activation of RankL gene expression by PKA- and gp130-inducers is mediated via common regulatory domains that also served to facilitate the activity of 1,25-(OH)₂D₃.