NF‐κB Has a Direct Role in Inhibiting Bmp‐ and Wnt‐Induced Matrix Protein Expression

The host response to pathogens through nuclear factor kappa B (NF-kappa B ) is an essential defense mechanism for eukaryotic organisms. NF-kappa 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-kappa B in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF-kappa B binding sites on osteocalcin (OC) or bone sialoprotein (Bsp) promoters rescues the negative impact of NF-kappa B on their transcription and that NF-kappa B can inhibit Wnt- and Bmp-induced OC and Bsp transcription, even when protein synthesis is inhibited, indicating a direct effect of NF-kappa B. This inhibition depends on p65-p50 NF-kappa B heterodimer formation and deacetylation by HDAC1 but is not affected by the noncanonical NF-kappa B pathway. Moreover, NF-kappa B reduces Runx2 and beta-catenin binding to OC/Bsp promoters independently of their nuclear localization. Thus, inflammatory signals stimulate the direct interaction of NF-kappa B with response elements to inhibit binding of b-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-kappa B activation. (C) 2015 American Society for Bone and Mineral Research.