PGC-1α is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts

Jeanne Nervina, Clara E. Magyar, Flavia Q. Pirih, Sotirios Tetradis

Research output: Contribution to journalArticle

Abstract

Parathyroid hormone (PTH) potently activates cAMP-protein kinase A (PKA)-driven molecular cascades in osteoblasts. The NR4A/NGFI-B orphan nuclear receptor (NR) Nurr1 is a PTH-induced, cAMP-responsive primary response gene (PRG) that transactivates osteocalcin (Ocn) expression through a putative NGFI-B response element (NBRE) in the proximal promoter. As a true orphan NR, Nurr1's expression level and coactivator recruitment regulate its transactivation capacity. We postulated that Nurr1's induction through cAMP-PKA signaling might favor a coactivator that is likewise cAMP-dependent. A possible candidate is the cAMP-inducible coactivator PPARγ coactivator-1α (PGC-1α). We hypothesize that PGC-1α is a PTH-induced PRG that synergizes with Nurr1 to induce target gene transcription in osteoblasts. We show that 10 nM PTH for 2 h maximally induced PGC-1α mRNA in primary mouse osteoblasts (MOBs) and calvariae. Selective signaling agonists and antagonists demonstrated that PTH induced PGC-1α mRNA primarily through the cAMP-PKA pathway. Protein synthesis inhibition sustained PTH-induced PGC-1α expression. PGC-1α enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively. This synergy required Nurr1-DNA binding, since a mutation of the Ocn promoter NBRE abolished both Nurr1- and Nurr1-PGC-1α-induced transactivation. Using GST pull-down assays, PGC-1α directly interacted with in vitro-generated and nuclear Nurr1. We conclude that PGC-1α is a PTH-induced, cAMP-dependent PRG that directly synergizes with Nurr1 to transactivate target genes in osteoblasts. Taken together with published data, our findings suggest that Nurr1 and PGC-1α may be pivotal mediators of cAMP-induced osteoblast gene expression and osteoblast function.

Original languageEnglish (US)
Pages (from-to)1018-1025
Number of pages8
JournalBone
Volume39
Issue number5
DOIs
StatePublished - Nov 2006

Fingerprint

Parathyroid Hormone
Osteoblasts
Nuclear Receptor Subfamily 4, Group A, Member 2
Osteocalcin
Cyclic AMP-Dependent Protein Kinases
Transcriptional Activation
Genes
Response Elements
Luciferases
Nuclear Receptor Subfamily 4, Group A, Member 1
Messenger RNA
Peroxisome Proliferator-Activated Receptors
Skull
Gene Expression
Mutation
DNA
Proteins

Keywords

  • Nurr1
  • Osteoblasts
  • Parathyroid hormone
  • PGC-1α
  • Transcription

ASJC Scopus subject areas

  • Physiology
  • Hematology

Cite this

PGC-1α is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. / Nervina, Jeanne; Magyar, Clara E.; Pirih, Flavia Q.; Tetradis, Sotirios.

In: Bone, Vol. 39, No. 5, 11.2006, p. 1018-1025.

Research output: Contribution to journalArticle

Nervina, Jeanne ; Magyar, Clara E. ; Pirih, Flavia Q. ; Tetradis, Sotirios. / PGC-1α is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. In: Bone. 2006 ; Vol. 39, No. 5. pp. 1018-1025.
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abstract = "Parathyroid hormone (PTH) potently activates cAMP-protein kinase A (PKA)-driven molecular cascades in osteoblasts. The NR4A/NGFI-B orphan nuclear receptor (NR) Nurr1 is a PTH-induced, cAMP-responsive primary response gene (PRG) that transactivates osteocalcin (Ocn) expression through a putative NGFI-B response element (NBRE) in the proximal promoter. As a true orphan NR, Nurr1's expression level and coactivator recruitment regulate its transactivation capacity. We postulated that Nurr1's induction through cAMP-PKA signaling might favor a coactivator that is likewise cAMP-dependent. A possible candidate is the cAMP-inducible coactivator PPARγ coactivator-1α (PGC-1α). We hypothesize that PGC-1α is a PTH-induced PRG that synergizes with Nurr1 to induce target gene transcription in osteoblasts. We show that 10 nM PTH for 2 h maximally induced PGC-1α mRNA in primary mouse osteoblasts (MOBs) and calvariae. Selective signaling agonists and antagonists demonstrated that PTH induced PGC-1α mRNA primarily through the cAMP-PKA pathway. Protein synthesis inhibition sustained PTH-induced PGC-1α expression. PGC-1α enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively. This synergy required Nurr1-DNA binding, since a mutation of the Ocn promoter NBRE abolished both Nurr1- and Nurr1-PGC-1α-induced transactivation. Using GST pull-down assays, PGC-1α directly interacted with in vitro-generated and nuclear Nurr1. We conclude that PGC-1α is a PTH-induced, cAMP-dependent PRG that directly synergizes with Nurr1 to transactivate target genes in osteoblasts. Taken together with published data, our findings suggest that Nurr1 and PGC-1α may be pivotal mediators of cAMP-induced osteoblast gene expression and osteoblast function.",
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AU - Tetradis, Sotirios

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N2 - Parathyroid hormone (PTH) potently activates cAMP-protein kinase A (PKA)-driven molecular cascades in osteoblasts. The NR4A/NGFI-B orphan nuclear receptor (NR) Nurr1 is a PTH-induced, cAMP-responsive primary response gene (PRG) that transactivates osteocalcin (Ocn) expression through a putative NGFI-B response element (NBRE) in the proximal promoter. As a true orphan NR, Nurr1's expression level and coactivator recruitment regulate its transactivation capacity. We postulated that Nurr1's induction through cAMP-PKA signaling might favor a coactivator that is likewise cAMP-dependent. A possible candidate is the cAMP-inducible coactivator PPARγ coactivator-1α (PGC-1α). We hypothesize that PGC-1α is a PTH-induced PRG that synergizes with Nurr1 to induce target gene transcription in osteoblasts. We show that 10 nM PTH for 2 h maximally induced PGC-1α mRNA in primary mouse osteoblasts (MOBs) and calvariae. Selective signaling agonists and antagonists demonstrated that PTH induced PGC-1α mRNA primarily through the cAMP-PKA pathway. Protein synthesis inhibition sustained PTH-induced PGC-1α expression. PGC-1α enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively. This synergy required Nurr1-DNA binding, since a mutation of the Ocn promoter NBRE abolished both Nurr1- and Nurr1-PGC-1α-induced transactivation. Using GST pull-down assays, PGC-1α directly interacted with in vitro-generated and nuclear Nurr1. We conclude that PGC-1α is a PTH-induced, cAMP-dependent PRG that directly synergizes with Nurr1 to transactivate target genes in osteoblasts. Taken together with published data, our findings suggest that Nurr1 and PGC-1α may be pivotal mediators of cAMP-induced osteoblast gene expression and osteoblast function.

AB - Parathyroid hormone (PTH) potently activates cAMP-protein kinase A (PKA)-driven molecular cascades in osteoblasts. The NR4A/NGFI-B orphan nuclear receptor (NR) Nurr1 is a PTH-induced, cAMP-responsive primary response gene (PRG) that transactivates osteocalcin (Ocn) expression through a putative NGFI-B response element (NBRE) in the proximal promoter. As a true orphan NR, Nurr1's expression level and coactivator recruitment regulate its transactivation capacity. We postulated that Nurr1's induction through cAMP-PKA signaling might favor a coactivator that is likewise cAMP-dependent. A possible candidate is the cAMP-inducible coactivator PPARγ coactivator-1α (PGC-1α). We hypothesize that PGC-1α is a PTH-induced PRG that synergizes with Nurr1 to induce target gene transcription in osteoblasts. We show that 10 nM PTH for 2 h maximally induced PGC-1α mRNA in primary mouse osteoblasts (MOBs) and calvariae. Selective signaling agonists and antagonists demonstrated that PTH induced PGC-1α mRNA primarily through the cAMP-PKA pathway. Protein synthesis inhibition sustained PTH-induced PGC-1α expression. PGC-1α enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively. This synergy required Nurr1-DNA binding, since a mutation of the Ocn promoter NBRE abolished both Nurr1- and Nurr1-PGC-1α-induced transactivation. Using GST pull-down assays, PGC-1α directly interacted with in vitro-generated and nuclear Nurr1. We conclude that PGC-1α is a PTH-induced, cAMP-dependent PRG that directly synergizes with Nurr1 to transactivate target genes in osteoblasts. Taken together with published data, our findings suggest that Nurr1 and PGC-1α may be pivotal mediators of cAMP-induced osteoblast gene expression and osteoblast function.

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