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Title

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

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Published in Bone. 2009, vol. 45, no. 4, p. 716-25
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 AnimalsArrestins/metabolismCell Differentiation/drug effectsCluster AnalysisGene Expression ProfilingGene Expression Regulation/drug effectsGene Regulatory Networks/drug effectsMiceNF-kappa B/geneticsOsteoblasts/cytology/drug effects/enzymologyParathyroid Hormone/pharmacologyReverse Transcriptase Polymerase Chain ReactionP38 Mitogen-Activated Protein Kinases/metabolism
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PMID: 19560570
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Structures
Research group Génétique des Ostéoporoses (544)
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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. 716-25. https://archive-ouverte.unige.ch/unige:5337

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Deposited on : 2010-03-04

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