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

Bone. 2009 Oct;45(4):716-25. doi: 10.1016/j.bone.2009.06.020. Epub 2009 Jun 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Osteoblasts / drug effects
  • Osteoblasts / enzymology*
  • Parathyroid Hormone / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • beta-Arrestin 2
  • beta-Arrestins
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Arrb2 protein, mouse
  • Arrestins
  • NF-kappa B
  • Parathyroid Hormone
  • beta-Arrestin 2
  • beta-Arrestins
  • p38 Mitogen-Activated Protein Kinases