Connexin43 regulates osteoprotegerin expression via ERK1/2 -dependent recruitment of Sp1

Copyright © 2019 Elsevier Inc. All rights reserved..

In bone, connexin43 expression in cells of the osteoblast lineage plays an important role in restraining osteoclastogenesis and bone resorption. While there is a consensus around the notion that the anti-osteoclastogenic factor, osteoprotegerin, is a driver of this effect, how connexin43 regulates osteoprotegerin gene expression is unclear. Here, we show that loss of connexin43 decreased osteoprotegerin gene expression and reduced ERK1/2 activation. Conversely, overexpression of connexin43 increased osteoprotegerin expression and enhanced ERK1/2 activation. This increase in phospho-ERK1/2 is required for connexin43 to induce transcription from the osteoprotegerin proximal promoter. Connexin43 increased promoter activity via a specific 200 base pair region of the osteoprotegerin promoter located at -1486 to -1286 with respect to the transcriptional start site, a region which includes four Sp1 binding elements. Further, activation of this promoter region required an intact functional connexin43, as hypomorphic or dominant negative connexin43 mutant constructs, including one with increased hemichannel activity, were unable to stimulate osteoprotegerin expression as strongly as wild type connexin43. Using chromatin immunoprecipitations, we show that connexin43 expression enhanced the recruitment of Sp1, but not Runx2, to the osteoprotegerin proximal promoter. In total, these data show that connexin43-dependent gap junctional communication among osteoblast cells permits efficient ERK1/2 activation. ERK1/2 signaling promotes the recruitment of the potent transcriptional activator, Sp1, to the osteoprotegerin proximal promoter, resulting in robust transcription of anti-osteoclastogenic factor, osteoprotegerin.

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:509

Enthalten in:

Biochemical and biophysical research communications - 509(2019), 3 vom: 12. Feb., Seite 728-733

Sprache:

Englisch

Beteiligte Personen:

Gupta, Aditi [VerfasserIn]
Leser, Jenna M [VerfasserIn]
Gould, Nicole R [VerfasserIn]
Buo, Atum M [VerfasserIn]
Moorer, Megan C [VerfasserIn]
Stains, Joseph P [VerfasserIn]

Links:

Volltext

Themen:

Connexin 43
Connexin43
EC 2.7.11.24
Gap junctions
Journal Article
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Osteoblast
Osteoclast
Osteoprotegerin
Research Support, N.I.H., Extramural
Sp1 Transcription Factor

Anmerkungen:

Date Completed 04.11.2019

Date Revised 09.03.2020

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.bbrc.2018.12.173

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM29254880X