title: NF-κB Has a Direct Role in Inhibiting Bmp- and Wnt-Induced Matrix Protein Expression.
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.
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Rohinton S
authors.initials: RS
authors.lastname: Tarapore
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pacios
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Wenmei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reid
authors.affiliation: Division of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hancheng
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Mattos
authors.affiliation: Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA, USA.
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D020218:Response Elements / Q000502:physiology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D016326:Extracellular Matrix Proteins; D052002:NF-kappa B p50 Subunit; C498144:Rela protein, mouse; C493716:Runx2 protein, mouse; D051996:Transcription Factor RelA; D051153:Wnt Proteins; D051176:beta Catenin; C073701:Nfkb1 protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
keywords: BMP; BONE FORMATION; INFLAMMATION; MATRIX PROTEINS; NF-κB; OSTEOBLASTS; TNFα; WNT