Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

1-2016

Publication Source

Journal of Bone and Mineral Research

Volume

31

Issue

1

Start Page

52

Last Page

64

DOI

10.1002/jbmr.2592

Abstract

The host response to pathogens through nuclear factor κB (NF-κB) is an essential defense mechanism for eukaryotic organisms. NF-κB-mediated host responses inhibit bone and other connective tissue synthesis and are thought to affect the transcription of matrix proteins through multiple indirect pathways. We demonstrate that inhibiting NF-κB in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF-κB binding sites on osteocalcin (OC) or bone sialoprotein (Bsp) promoters rescues the negative impact of NF-κB on their transcription and that NF-κB can inhibit Wnt- and Bmp-induced OC and Bsp transcription, even when protein synthesis is inhibited, indicating a direct effect of NF-κB. This inhibition depends on p65-p50 NF-κB heterodimer formation and deacetylation by HDAC1 but is not affected by the noncanonical NF-κB pathway. Moreover, NF-κB reduces Runx2 and β-catenin binding to OC/Bsp promoters independently of their nuclear localization. Thus, inflammatory signals stimulate the direct interaction of NF-κB with response elements to inhibit binding of β-catenin and Runx2 binding to nearby consensus sites and reduce expression of matrix proteins. This direct mechanism provides a new explanation for the rapid decrease in new bone formation after inflammation-related NF-κB activation.

Copyright/Permission Statement

This is the peer reviewed version of the following article: Tarapore, R. S., Lim, J., Tian, C., Pacios, S., Xiao, W., Reid, D., … Graves, D. T. (2016). NF-κB Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research, 31(1), 52–64. http://doi.org/10.1002/jbmr.2592, which has been published in final form at http://dx.doi.org/10.1002/jbmr.2592. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving [http://olabout.wiley.com/WileyCDA/Section/id-820227.html#terms].

Keywords

bone formation, bmp, inflammation, matrix proteins, osteoblasts, tnfa, nf-kb, wnt

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Date Posted: 01 March 2022

This document has been peer reviewed.