title: Loading-related regulation of transcription factor EGR2/Krox-20 in bone cells is ERK1/2 protein-mediated and prostaglandin, Wnt signaling pathway-, and insulin-like growth factor-I axis-dependent.
abstract: Of the 1,328 genes revealed by microarray to be differentially regulated by disuse, or at 8 h following a single short period of osteogenic loading of the mouse tibia, analysis by predicting associated transcription factors from annotated affinities revealed the transcription factor EGR2/Krox-20 as being more closely associated with more pathways and functions than any other. Real time quantitative PCR confirmed up-regulation of Egr2 mRNA expression by loading of the tibia in vivo. In vitro studies where strain was applied to primary cultures of mouse tibia-derived osteoblastic cells and the osteoblast UMR106 cell line also showed up-regulation of Egr2 mRNA expression. In UMR106 cells, inhibition of β1/β3 integrin function had no effect on strain-related Egr2 expression, but it was inhibited by a COX2-selective antagonist and imitated by exogenous prostaglandin E2 (PGE2). This response to PGE(2) was mediated chiefly through the EP1 receptor and involved stimulation of PKC and attenuation by cAMP/PKA. Neither activators nor inhibitors of nitric oxide, estrogen signaling, or LiCl had any effect on Egr2 mRNA expression, but it was increased by both insulin-like growth factor-1 and high, but not low, dose parathyroid hormone and exogenous Wnt-3a. The increases by strain, PGE2, Wnt-3a, and phorbol 12-myristate 13-acetate were attenuated by inhibition of MEK-1. EGR2 appears to be involved in many of the signaling pathways that constitute early responses of bone cells to strain. These pathways all have multiple functions. Converting their strain-related responses into coherent "instructions" for adaptive (re)modeling is likely to depend upon their contextual activation, suppression, and interaction probably on more than one occasion.
authors: Department of Veterinary Basic Sciences, Royal Veterinary College, London, NW1 0TU, United Kingdom. gzaman@rvc.ac.uk
authors: Gul
authors: G
authors: Zaman
authors: Andrew
authors: A
authors: Sunters
authors: Gabriel L
authors: GL
authors: Galea
authors: Behzad
authors: B
authors: Javaheri
authors: Leanne K
authors: LK
authors: Saxon
authors: Alaa
authors: A
authors: Moustafa
authors: Victoria J
authors: VJ
authors: Armstrong
authors: Joanna S
authors: JS
authors: Price
authors: Lance E
authors: LE
authors: Lanyon
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D019012:Integrin beta1; D039661:Integrin beta3; C545636:Ptger1 protein, mouse; D012333:RNA, Messenger; D058306:Receptors, Prostaglandin E, EP1 Subtype; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C519530:insulin-like growth factor-1, mouse; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate