Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts

Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding prote...

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Veröffentlicht in:PloS one 2011-06, Vol.6 (6), p.e20780
Hauptverfasser: Zhang, Rongrong, Edwards, James R, Ko, Seon-Yle, Dong, Shanshan, Liu, Hongbin, Oyajobi, Babatunde O, Papasian, Christopher, Deng, Hong-Wen, Zhao, Ming
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container_issue 6
container_start_page e20780
container_title PloS one
container_volume 6
creator Zhang, Rongrong
Edwards, James R
Ko, Seon-Yle
Dong, Shanshan
Liu, Hongbin
Oyajobi, Babatunde O
Papasian, Christopher
Deng, Hong-Wen
Zhao, Ming
description Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts.
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Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. 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Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. 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Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21695256</pmid><doi>10.1371/journal.pone.0020780</doi><tpages>e20780</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
Antigens
Base Sequence
Biocompatibility
Bioinformatics
Biology
Bone density
Bone mass
Bone morphogenetic protein 2
Bone Morphogenetic Protein 2 - genetics
Bone Morphogenetic Protein 2 - metabolism
Bone morphogenetic proteins
Cell Differentiation - drug effects
Cell Line
Cell lines
Chromatin
Clonal deletion
Cyclic adenosine monophosphate
Cyclic AMP response element-binding protein
Cyclic AMP Response Element-Binding Protein - metabolism
Differentiation
Electrophoretic mobility
Gene deletion
Gene expression
Gene Expression Regulation - drug effects
Gene regulation
Genetic aspects
Immunoprecipitation
Kinases
Medicine
Mice
Molecular Sequence Data
Mutation
Neurodegeneration
Osteoblastogenesis
Osteoblasts
Osteoblasts - cytology
Osteoblasts - drug effects
Osteoblasts - metabolism
Parathyroid
Parathyroid hormone
Parathyroid Hormone - metabolism
Parathyroid Hormone - pharmacology
Parathyroid hormones
Pharmacology
Phosphorylation
Phosphorylation - drug effects
Promoter Regions, Genetic
Protein binding
Proteins
Rodents
Signal transduction
Signal Transduction - drug effects
Signaling
Transcription (Genetics)
Transcription, Genetic - drug effects
Transcriptional Activation - drug effects
Transcriptional Activation - genetics
Transgenic animals
Up-Regulation - genetics
title Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts
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