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PMID: 19560570 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Bone ·Vol. 45 ·No. 4 ·2009-10-00 ·Pages 716-25

Bianchi EN, Ferrari SL

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.

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,drug effects,enzymology Parathyroid Hormone/pharmacology Reverse Transcriptase Polymerase Chain Reaction beta-Arrestin 2 beta-Arrestins p38 Mitogen-Activated Protein Kinases/metabolism
Chemicals
Arrb2 protein, mouse Arrestins NF-kappa B Parathyroid Hormone beta-Arrestin 2 beta-Arrestins p38 Mitogen-Activated Protein Kinases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Bianchi Estelle N
Department of Rehabilitation and Geriatrics, WHO Center for Osteoporosis Prevention, Geneva University Hospitals and University of Geneva, Faculty of Medicine, Switzerland. bianchi6@etu.unige.ch
Ferrari Serge L
References (46)
46 references, click to expand
  1. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.
    N Engl J Med. 2001 May 10;344(19):1434-41 PMID: 11346808
  2. Proline-rich motifs in the parathyroid hormone (PTH)/PTH-related protein receptor C terminus mediate scaffolding of c-Src with beta-arrestin2 for ERK1/2 activation.
    J Biol Chem. 2006 Dec 15;281(50):38181-8 PMID: 17038311
  3. Stimulation of extracellular signal-regulated kinases and proliferation in rat osteoblastic cells by parathyroid hormone is protein kinase C-dependent.
    J Biol Chem. 2001 Mar 9;276(10):7586-92 PMID: 11108712
  4. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.
    Nature. 2000 Dec 7;408(6813):720-3 PMID: 11130073
  5. Evidence for a regulatory role of inducible cAMP early repressor in protein kinase a-mediated enhancement of vitamin D receptor expression and modulation of hormone action.
    Mol Endocrinol. 2002 Sep;16(9):2052-64 PMID: 12198242
  6. 3',5'-Cyclic adenosine monophosphate activation in osteoblastic cells: effects on parathyroid hormone-1 receptors and osteoblastic differentiation in vitro.
    Endocrinology. 1999 Jul;140(7):3154-62 PMID: 10385409
  7. Anabolic action of parathyroid hormone is skeletal site specific at the tissue and cellular levels in mice.
    J Bone Miner Res. 2002 May;17(5):808-16 PMID: 12009011
  8. Cyclic AMP induces insulin-like growth factor I synthesis in osteoblast-enriched cultures.
    J Biol Chem. 1990 Sep 15;265(26):15353-6 PMID: 1697590
  9. Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells.
    J Clin Invest. 1997 Jun 15;99(12):2961-70 PMID: 9185520
  10. Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells.
    Bone. 2007 Jul;41(1):59-67 PMID: 17434817
  11. Osteoclast-derived activity in the coupling of bone formation to resorption.
    Trends Mol Med. 2005 Feb;11(2):76-81 PMID: 15694870
  12. Beta-Arrestin2 regulates RANKL and ephrins gene expression in response to bone remodeling in mice.
    J Bone Miner Res. 2009 May;24(5):775-84 PMID: 19113915
  13. Interactions of PTH and PTHrP with the PTH/PTHrP receptor and with downstream signaling pathways: exceptions that provide the rules.
    J Bone Miner Res. 1999 Feb;14(2):173-7 PMID: 9933469
  14. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women.
    J Clin Invest. 2003 Apr;111(8):1221-30 PMID: 12697741
  15. Historical review: a brief history and personal retrospective of seven-transmembrane receptors.
    Trends Pharmacol Sci. 2004 Aug;25(8):413-22 PMID: 15276710
  16. Receptors for PTH and PTHrP: their biological importance and functional properties.
    Am J Physiol. 1999 Nov;277(5):F665-75 PMID: 10564229
  17. Truncation of the amino terminus of PTH alters its anabolic activity on bone in vivo.
    Bone. 1996 Nov;19(5):469-77 PMID: 8922645
  18. Molecular profile of catabolic versus anabolic treatment regimens of parathyroid hormone (PTH) in rat bone: an analysis by DNA microarray.
    J Cell Biochem. 2005 May 15;95(2):403-18 PMID: 15779007
  19. Minireview: the OPG/RANKL/RANK system.
    Endocrinology. 2001 Dec;142(12):5050-5 PMID: 11713196
  20. Skeletal disease in primary hyperparathyroidism.
    J Bone Miner Res. 1989 Jun;4(3):283-91 PMID: 2763869
  21. New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases.
    Clin Chem. 1999 Jan;45(1):7-17 PMID: 9895331
  22. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling.
    Science. 2003 Sep 5;301(5638):1394-7 PMID: 12958365
  23. ArrayExpress--a public repository for microarray gene expression data at the EBI.
    Nucleic Acids Res. 2003 Jan 1;31(1):68-71 PMID: 12519949
  24. Beta-arrestin-2 regulates the development of allergic asthma.
    J Clin Invest. 2003 Aug;112(4):566-74 PMID: 12925697
  25. Parathyroid hormone inhibits c-Jun N-terminal kinase activity in rat osteoblastic cells by a protein kinase A-dependent pathway.
    Endocrinology. 2002 May;143(5):1880-8 PMID: 11956171
  26. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein.
    J Biol Chem. 2002 Dec 13;277(50):48868-75 PMID: 12364326
  27. Analysis of transcriptional regulation of the small leucine rich proteoglycans.
    Mol Vis. 2004 Oct 07;10:758-72 PMID: 15496828
  28. G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization.
    J Biol Chem. 1998 Jul 24;273(30):18677-80 PMID: 9668034
  29. Transforming growth factor-beta1 to the bone.
    Endocr Rev. 2005 Oct;26(6):743-74 PMID: 15901668
  30. Robust estimators for expression analysis.
    Bioinformatics. 2002 Dec;18(12):1585-92 PMID: 12490442
  31. Bone response to intermittent parathyroid hormone is altered in mice null for {beta}-Arrestin2.
    Endocrinology. 2005 Apr;146(4):1854-62 PMID: 15705780
  32. Biochemical characterization with parathormone and calcitonin of isolated bone cells: provisional identification of osteoclasts and osteoblasts.
    Endocrinology. 1976 Aug;99(2):526-34 PMID: 182458
  33. Endocytosis of ligand-human parathyroid hormone receptor 1 complexes is protein kinase C-dependent and involves beta-arrestin2. Real-time monitoring by fluorescence microscopy.
    J Biol Chem. 1999 Oct 15;274(42):29968-75 PMID: 10514480
  34. Parathyroid hormone fragments may stimulate bone growth in ovariectomized rats by activating adenylyl cyclase.
    J Bone Miner Res. 1994 Aug;9(8):1179-89 PMID: 7976500
  35. Beta-arrestin-dependent parathyroid hormone-stimulated extracellular signal-regulated kinase activation and parathyroid hormone type 1 receptor internalization.
    Endocrinology. 2007 Aug;148(8):4073-9 PMID: 17525124
  36. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation.
    J Biol Chem. 2006 Apr 21;281(16):10856-64 PMID: 16492667
  37. Determination of dual effects of parathyroid hormone on skeletal gene expression in vivo by microarray and network analysis.
    J Biol Chem. 2007 Nov 9;282(45):33086-97 PMID: 17690103
  38. An intact N terminus is required for the anabolic action of parathyroid hormone on adult female rats.
    J Bone Miner Res. 1997 Mar;12(3):384-92 PMID: 9076581
  39. Selective ligand-induced stabilization of active and desensitized parathyroid hormone type 1 receptor conformations.
    J Biol Chem. 2002 Oct 11;277(41):38524-30 PMID: 12107160
  40. The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts.
    J Cell Biochem. 2009 May 1;107(1):144-54 PMID: 19259985
  41. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways.
    Mol Cell. 2004 May 7;14(3):303-17 PMID: 15125834
  42. PTH and PTHrP effects on the skeleton.
    Rev Endocr Metab Disord. 2000 Nov;1(4):331-41 PMID: 11706747
  43. Analysis of high density expression microarrays with signed-rank call algorithms.
    Bioinformatics. 2002 Dec;18(12):1593-9 PMID: 12490443
  44. Parathyroid hormone: a double-edged sword for bone metabolism.
    Trends Endocrinol Metab. 2004 Mar;15(2):60-5 PMID: 15036251
  45. beta-Arrestin2 regulates the differential response of cortical and trabecular bone to intermittent PTH in female mice.
    J Bone Miner Res. 2005 Apr;20(4):635-43 PMID: 15765183
  46. Continuous parathyroid hormone induces cortical porosity in the rat: effects on bone turnover and mechanical properties.
    J Bone Miner Res. 2004 Jul;19(7):1165-71 PMID: 15177000
Article Info
Journal
Bone
Abbr.
Bone
ISSN
1873-2763
DOI
10.1016/j.bone.2009.06.020
Email
bianchi6@etu.unige.ch
Published
2009-10-00
Epub
2009-00-25
Pages
716-25
Language
English
Region
United States
NLM ID
8504048
PMCID
PMC2741591
Subset
IM
Grants
NIAMS NIH HHS · R01 AR049265 · United States
NIAMS NIH HHS · R01 AR049265-04 · United States
External Links
PubMed source DOI: 10.1016/j.bone.2009.06.020 PMC Full Text View journal details
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