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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone and Bones / cytology
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Bone and Bones / metabolism*
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Carcinogens / pharmacology
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Cell Line
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Cyclic AMP / genetics
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / genetics
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Dinoprostone / metabolism*
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Early Growth Response Protein 2 / genetics
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Early Growth Response Protein 2 / metabolism*
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Female
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Integrin beta1 / genetics
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Integrin beta1 / metabolism
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Integrin beta3 / genetics
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Integrin beta3 / metabolism
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 1 / metabolism
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Mice
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Nitric Oxide / genetics
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Nitric Oxide / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Prostaglandin E, EP1 Subtype / genetics
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Receptors, Prostaglandin E, EP1 Subtype / metabolism
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Tetradecanoylphorbol Acetate / pharmacology
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Up-Regulation / drug effects
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Up-Regulation / physiology*
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Wnt Signaling Pathway / drug effects
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Wnt Signaling Pathway / physiology*
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Wnt3A Protein / genetics
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Wnt3A Protein / metabolism
Substances
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Carcinogens
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Early Growth Response Protein 2
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Egr2 protein, mouse
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Integrin beta1
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Integrin beta3
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Ptger1 protein, mouse
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RNA, Messenger
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Receptors, Prostaglandin E, EP1 Subtype
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Wnt3A Protein
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Wnt3a protein, mouse
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insulin-like growth factor-1, mouse
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Nitric Oxide
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Insulin-Like Growth Factor I
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Cyclic AMP
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Cyclic AMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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Map2k1 protein, mouse
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Dinoprostone
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Tetradecanoylphorbol Acetate