期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 31, 期 1, 页码 52-64出版社
WILEY
DOI: 10.1002/jbmr.2592
关键词
BONE FORMATION; BMP; INFLAMMATION; MATRIX PROTEINS; OSTEOBLASTS; TNFA; NF-kappa B; WNT
资金
- National Institutes of Health [DE-017732, AR-060055]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR060055, R01AR063089] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [R01DE019412, R01DE017732, R01DE021921] Funding Source: NIH RePORTER
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.
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