en
Scientific article
English

Beta-arrestin2 regulates parathyroid hormone effects on a p38 MAPK and NFkappaB gene expression network in osteoblasts

Published inBone, vol. 45, no. 4, p. 716-725
Publication date2009
Abstract

Interaction of the cytoplasmic adaptor molecule beta-arrestin2 with the activated parathyroid hormone (PTH)/PTHrP receptor inhibits G protein mediated signaling and triggers MAPKs signaling. In turn, the effects of both intermittent (i.) and continuous (c.) PTH on bone are altered in beta-arrestin2-deficient (Arrb2(-/-)) mice. To elucidate the expression profile of bone genes responsive to PTH and targeted for regulation by beta-arrestin2, we performed microarray analysis using total RNA from primary osteoblastic cells isolated from wild-type (WT) and Arrb2(-/-) mice. By comparing gene expression profiles in cells exposed to i.PTH, c.PTH or vehicle (Veh) for 2 weeks, we found that i.PTH specifically up-regulated 215 sequences (including beta-arrestin2) and down-regulated 200 sequences in WT cells, about two-thirds of them being under the control of beta-arrestin2. In addition, beta-arrestin2 appeared necessary to the down-regulation of a genomic cluster coding for small leucin-rich proteins (SLRPs) including osteoglycin, osteomodulin and asporin. Pathway analyses identified a main gene network centered on p38 MAPK and NFkappaB that requires beta-arrestin2 for up- or down-regulation by i.PTH, and a smaller network of PTH-regulated genes centered on TGFB1, that is normally repressed by beta-arrestin2. In contrast the expression of some known PTH gene targets regulated by the cAMP/PKA pathway was not affected by the presence or absence of beta-arrestin2 in osteoblasts. These results indicate that beta-arrestin2 targets prominently p38 MAPK- and NFkappaB-dependent expression in osteoblasts exposed to i.PTH, and delineates new molecular mechanisms to explain the anabolic and catabolic effects of PTH on bone.

Keywords
  • Animals
  • Arrestins/metabolism
  • Cell Differentiation/drug effects
  • Cluster Analysis
  • Gene Expression Profiling
  • Gene Expression Regulation/drug effects
  • Gene Regulatory Networks/drug effects
  • Mice
  • NF-kappa B/genetics
  • Osteoblasts/cytology/drug effects/enzymology
  • Parathyroid Hormone/pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • P38 Mitogen-Activated Protein Kinases/metabolism
Citation (ISO format)
BIANCHI, Estelle, FERRARI, Serge Livio. Beta-arrestin2 regulates parathyroid hormone effects on a p38 MAPK and NFkappaB gene expression network in osteoblasts. In: Bone, 2009, vol. 45, n° 4, p. 716–725. doi: 10.1016/j.bone.2009.06.020
Main files (1)
Article (Published version)
accessLevelRestricted
Secondary files (4)
Identifiers
ISSN of the journal1873-2763
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