{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:53:00Z","timestamp":1789138380575,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2001,12,7]],"date-time":"2001-12-07T00:00:00Z","timestamp":1007683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Osteoprotegerin (OPG), a secreted member of the tumor necrosis receptor superfamily, is a potent inhibitor of osteoclast formation and bone resorption. Parathyroid hormone (PTH), a potent inducer of osteoclast formation, suppresses OPG mRNA expression in vitro and in vivo. To determine the molecular basis of this inhibition, we analyzed the effects of PTH on the human OPG promoter (\u22125917 to +19) fused with \u03b2\u2010galactosidase reporter gene in stable and transient transfections into rat osteoblast\u2010like UMR106 cells. The effect of PTH on OPG promoter expression was biphasic and concentration\u2010dependent. PTH (1\u2013100 nM) induced the transcriptional activity of the OPG promoter (1.7\u2010fold) at 8 h followed by a gradual decrease with maximal inhibition (6.6\u2010fold) at 24\u201348 h. To ascertain the signal transduction pathways mediating PTH (1\u201338) effects on OPG gene expression, we compared the effects of PTH with PTH analogs, parathyroid hormone\u2010related protein 1\u201334 (PTHrP 1\u201334), forskolin, 3\u2010isobutyl\u20101\u2010methylxanthine (IBMX), dibutyryl cAMP, phorbol\u201012\u2010myristate\u201013\u2010acetate (PMA), thapsigargin and calcium ionophore A23187. PTH 1\u201331 and PTHrP 1\u201334, which stimulate the cAMP\/PKA pathway, and other activators of cAMP\/PKA, forskolin, IBMX, N<jats:sup>6<\/jats:sup>, O<jats:sup>2\u2032<\/jats:sup>\u2010dibityryl adenosine 3\u2032,5\u2032\u2010cyclic monophosphate (dibutyryl cAMP), all elicited a similar biphasic response on OPG promoter expression. PTH analogs PTH 3\u201334 and PTH 7\u201334, that do not stimulate cAMP production, had no effect on OPG expression. In contrast, phorbol\u201012\u2010myristate\u201013\u2010acetate (PMA), an activator of PKC, stimulated OPG promoter expression, while thapsigargin and calcium ionophore A23187, which increase intracellular Ca<jats:sup>2+<\/jats:sup>, showed a dose\u2010dependent inhibition of OPG promoter expression. To delineate the promoter sequences that mediate the inhibitory effects of PTH on OPG transcription, we analyzed systematic deletions of the OPG promoter for responsiveness in transient transfection assays. The major inhibitory effects of PTH were localized to 391 bp (\u2212372 to +19) of the proximal promoter. Deletions of the promoter region led to a complete loss of responsiveness. Taken together, these results demonstrate that the inhibitory effects of PTH on OPG are mediated at the transcriptional level through <jats:italic>cis<\/jats:italic> elements in the proximal promoter. The similar biphasic response of OPG to PTH, PTH 1\u201331, PTHrP 1\u201334, forskolin, IBMX and dibutyryl cAMP suggests that PTH regulates OPG transcription via activation of the cAMP\/PKA signal transduction pathway. J. Cell. Biochem. 84: 1\u201311, 2002. \u00a9 2001 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.1273","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T21:17:12Z","timestamp":1030310232000},"page":"1-11","source":"Crossref","is-referenced-by-count":27,"title":["Identification of signal transduction pathways and promoter sequences that mediate parathyroid hormone 1\u201338 inhibition of osteoprotegerin gene expression"],"prefix":"10.1002","volume":"84","author":[{"given":"David L.","family":"Halladay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca R.","family":"Miles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kannan","family":"Thirunavukkarasu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasan","family":"Chandrasekhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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