Abstract
Parathyroid hormone (PTH) stimulates osteoclast formation by binding to its receptor on stromal/osteoblastic cells and stimulating the production of receptor activator of NFkappaB ligand (RANKL) and inhibiting the expression of osteoprotegerin (OPG). However, the mechanisms through which PTH regulates these genes remain unknown. Here we report that PTH stimulated RANKL gene transcription and increased RANKL mRNA stability in murine stromal/osteoblastic cells stably expressing human PTH/PTH-related protein receptor 1. PTH also potently suppressed OPG mRNA in these cells. Cycloheximide did not block the effects of PTH on RANKL but did inhibit the suppression of OPG mRNA. Activation of protein kinase A (PKA) was necessary and sufficient for the effect of PTH on both genes. Conditional expression of a dominant-negative form of the transcription factor CREB, but not c-fos or Runx2, significantly reduced PTH stimulation of RANKL. CREB activity was also required for full stimulation of RANKL by oncostatin M or 1,25-dihydroxyvitamin D(3). Dominant-negative forms of CREB and c-fos reduced the suppression of OPG by PTH. These results demonstrate that PTH directly stimulates RANKL expression via a PKA-CREB pathway and that CREB may be a central regulator of RANKL expression. Furthermore, they suggest that PTH suppression of OPG involves CREB and c-fos.
Highlights
Parathyroid hormone (PTH) stimulates osteoclast formation by binding to its receptor on stromal/osteoblastic cells and stimulating the production of receptor activator of NFB ligand (RANKL) and inhibiting the expression of osteoprotegerin (OPG)
Introduction of the Human PTHR1 into a Murine Stromal/ Osteoblastic Cell Line Confers Robust Responsiveness to PTH— Some of the mechanistic studies we sought to perform required the use of a continuous cell line in which PTH strongly stimulates RANKL and inhibits OPG expression
Our results in UAMS-32P and primary bone marrow cells indicate that PTH directly stimulates RANKL transcription via cAMP activation of protein kinase A (PKA)
Summary
Vol 277, No 50, Issue of December 13, pp. 48868 –48875, 2002 Printed in U.S.A. Parathyroid Hormone Stimulates Receptor Activator of NFB Ligand and Inhibits Osteoprotegerin Expression via Protein Kinase A Activation of cAMP-response Element-binding Protein*. Parathyroid hormone (PTH) stimulates osteoclast formation by binding to its receptor on stromal/osteoblastic cells and stimulating the production of receptor activator of NFB ligand (RANKL) and inhibiting the expression of osteoprotegerin (OPG). Dominant-negative forms of CREB and c-fos reduced the suppression of OPG by PTH These results demonstrate that PTH directly stimulates RANKL expression via a PKACREB pathway and that CREB may be a central regulator of RANKL expression. Binding of PTH to PTHR1 on stromal/osteoblastic cells activates both the protein kinase A (PKA) and protein kinase C (PKC) pathways, and both pathways have been implicated in PTH-induced osteoclast formation in vitro [12] Activation of these pathways by PTH leads to activation of multiple transcription factors, including CREB, AP-1, and Runx2 [12]. Activation of the transcription factor CREB was shown to be required for full stimulation of RANKL by PTH, and both CREB and AP-1 are involved in PTH-suppression of OPG
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