NF-?B Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression.

ABSTRACT: The host response to pathogens through nuclear factor ?B (NF-?B) is an essential defense mechanism for eukaryotic organisms. NF-?B-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-?B in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF-?B binding sites on osteocalcin (OC) or bone sialoprotein (Bsp) promoters rescues the negative impact of NF-?B on their transcription and that NF-?B can inhibit Wnt- and Bmp-induced OC and Bsp transcription, even when protein synthesis is inhibited, indicating a direct effect of NF-?B. This inhibition depends on p65-p50 NF-?B heterodimer formation and deacetylation by HDAC1 but is not affected by the noncanonical NF-?B pathway. Moreover, NF-?B reduces Runx2 and ?-catenin binding to OC/Bsp promoters independently of their nuclear localization. Thus, inflammatory signals stimulate the direct interaction of NF-?B with response elements to inhibit binding of ?-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-?B activation.

SUBMITTER: Tarapore RS 

PROVIDER: S-EPMC4713353 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature