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.
| Original language | English |
|---|---|
| Pages (from-to) | 52-64 |
| Number of pages | 13 |
| Journal | Journal of Bone and Mineral Research |
| Volume | 31 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
Bibliographical note
Funding Information:We thank Dr Chawnshang Chang (University of Rochester) for OC reporter plasmid. We thank Dr Renny Franceschi (University of Michigan) for generously providing the antibody and reporter construct for bone sialoprotein. We thank Dr Rob Riccardi for his technical assistance and for generously donating the p65-, p50-, p65(S275A)-overexpressing plasmids. We also thank Jyothsna Meda for assistance in microscopy. This work was supported by grants DE-017732 and AR-060055 from the National Institutes of Health. Authors’ roles: RT planned the experimental design, conducted experiments, and wrote the manuscript. JL and TC conducted experiments. SP and WX conducted in vivo experiments. DR and MM analyzed data. HG gave technical suggestions. BY and CW generated and provided the transgenic mice. DG conceived the project, designed experiments, interpreted the data and wrote the manuscript.
Funding Information:
We thank Dr Chawnshang Chang (University of Rochester) for OC reporter plasmid. We thank Dr Renny Franceschi (University of Michigan) for generously providing the antibody and reporter construct for bone sialoprotein. We thank Dr Rob Riccardi for his technical assistance and for generously donating the p65-, p50-, p65(S275A)-overexpressing plasmids. We also thank Jyothsna Meda for assistance in microscopy. This work was supported by grants DE-017732 and AR-060055 from the National Institutes of Health. Authors? roles: RT planned the experimental design, conducted experiments, and wrote the manuscript. JL and TC conducted experiments. SP and WX conducted in vivo experiments. DR and MM analyzed data. HG gave technical suggestions. BY and CW generated and provided the transgenic mice. DG conceived the project, designed experiments, interpreted the data and wrote the manuscript.
Publisher Copyright:
© 2015 American Society for Bone and Mineral Research.
Keywords
- BMP
- BONE FORMATION
- INFLAMMATION
- MATRIX PROTEINS
- NF-κB
- OSTEOBLASTS
- TNFα
- WNT
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine
