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 PGE2 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.

Epidermal Growth Factor Receptor (EGFR) Signaling Promotes Proliferation and Survival in Osteoprogenitors by Increasing Early Growth Response 2 (EGR2) Expression

“…EGR2 expression in bone is strongly induced by loading, and its expression in cultured osteoblastic cells is also increased by strain (36). Moreover, major signaling pathways associated with loading and bone formation, such as prostaglandins, IGF-I, and Wnt3a, also rapidly increase EGR2 expression in osteoblasts (36). In contrast, glucocorticoid treatment leads to a drastic decrease in bone marrow osteoprogenitor number and an increase in osteoblast and osteocyte apoptosis in mice (2).…”

Primary gene response to mechanical loading in healing rat Achilles tendons

“…Egr1 also appears to be important in regulating the inflammatory response after injury (46). Both Egr1 and Egr2 can respond to a number of different types of stimuli including mechanical stimulation, wounding, and growth factors (2,13,16,32,46,48). A PASTAA (Predicting Associated Transcription factors from Annotated Affinities) analysis has shown that Egr2 appears more often in loading-related functions in bone than any other gene (48).…”

“…Both Egr1 and Egr2 can respond to a number of different types of stimuli including mechanical stimulation, wounding, and growth factors (2,13,16,32,46,48). A PASTAA (Predicting Associated Transcription factors from Annotated Affinities) analysis has shown that Egr2 appears more often in loading-related functions in bone than any other gene (48). Downstream targets for Egr1 and Egr2 include mediators of inflammation, coagulation, and different growth factors (2,16,46), and the gene expression for Egr1 and Egr2 can be induced by a number of different signaling pathways depending on which primary stimulus is involved (33).…”

Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the brain

“…The remaining 3 genes, Arc, Egr2 and Hspa1b, functionally involved in 'behavior', were also expected to participate in 'blood pressure' control, as well as in the development of ADHD. Arc plays a critical role in the consolidation of enduring synaptic plasticity and memory storage (28), while Egr2 encodes a transcription factor with 3 tandem C2H2-type zinc fingers [since defects in this gene are associated with neurological diseases, such as Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome, it has been suggested to play a role in learning and long-term potentiation (29,30)]. Hspa1b encodes a 70-kDa heat-shock protein, which is known to promote neurodegeneration in sporadic Parkinson's disease through its functional interaction with other Parkinson's disease-related genes (31).…”