ArticleArthritis research & therapy2015
CCAAT/enhancer-binding protein β promotes receptor activator of nuclear factor-kappa-B ligand (RANKL) expression and osteoclast formation in the synovium in rheumatoid arthritis.
Article in Arthritis research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 55 citations in OpenAlex.
- CCAAT/enhancer binding protein β and its role in autoimmune diseases: a promising therapeutic target.Journal of translational medicine · 2026Review
- Activating transcription factors: Orchestrators of macrophage biology in pathological settings (Review).International journal of molecular medicine · 2026Review
- Chicago Sky Blue 6B modulates MAPK/NF-kB pathway in rat knee osteoarthritis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Redox Pathogenesis in Rheumatic Diseases.ACR open rheumatology · 2024Review
- Review
- Concomitant induction of SLIT3 and microRNA-218-2 in macrophages by toll-like receptor 4 activation limits osteoclast commitment.Cell communication and signaling : CCS · 2023Article
- MicroRNAs-mediated regulation pathways in rheumatic diseases.Inflammopharmacology · 2023Review
- Emerging functions of C/EBPβ in breast cancer.Frontiers in oncology · 2023Review
- SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis.Molecular medicine (Cambridge, Mass.) · 2022Article
- The Potential Regulatory Mechanism of lncRNA 122K13.12 and lncRNA 326C3.7 in Ankylosing Spondylitis.Frontiers in molecular biosciences · 2021Article
- C/EBPß Isoform Specific Gene Regulation: It's a Lot more Complicated than you Think!Journal of mammary gland biology and neoplasia · 2020Review
- Elevated ATF4 Expression in Odontogenic Keratocysts Epithelia: Potential Involvement in Tissue Hypoxia and Stromal M2 Macrophage Infiltration.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2019Article
- Article
- eIF2α signaling regulates ischemic osteonecrosis through endoplasmic reticulum stress.Scientific reports · 2017Article
- Article
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5 authors at 1 institution in 1 country.
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Abstract
introductionCCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that is activated in the synovium in rheumatoid arthritis (RA) and promotes expression of various matrix metalloproteinases. In this study, we examined whether C/EBPβ mediates the expression of receptor activator of nuclear factor-kappa-B ligand (RANKL) and drives osteoclast formation in primary fibroblast-like synoviocytes (FLS) from RA patients. The cooperation of C/EBPβ and activation transcription factor-4 (ATF4) in the regulation of the RANKL promoter was also investigated.
methodsImmunofluorescence staining was performed for C/EBPβ, RANKL, and ATF4 in synovium from RA patients. Adenovirus expression vectors for two major isoforms, C/EBPβ-liver-enriched activator protein (LAP) and - liver-enriched inhibitory protein (LIP), or small interfering RNA for C/EBPβ, were used to manipulate C/EBPβ expression in RA-FLS. RA-FLS over-expressing C/EBPβ were co-cultured with peripheral blood mononuclear cells (PBMCs) to test osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. A promoter assay for RANKL, a chromatin immunoprecipitation (ChIP) assay and an immunoprecipitation (IP) assay were also performed.
resultsImmunofluorescence staining showed colocalization of C/EBPβ, ATF4 and RANKL in RA synovium. Western blotting revealed the expression of C/EBPβ-LAP and -LIP in RA-FLS. Over-expression of either C/EBPβ-LAP or -LIP significantly increased the expression of RANKL mRNA, while C/EBPβ-LIP down-regulated osteoprotegerin (OPG) mRNA. The RANKL/OPG mRNA ratio was significantly increased by C/EBPβ-LIP over-expression. Knockdown of C/EBPβ with siRNA decreased the expression of RANKL mRNA. The number of TRAP-positive multinucleated cells was increased in co-cultures of PBMCs and FLS over-expressing either C/EBPβ-LAP or -LIP, but was more significant with LIP. C/EBPβ-LIP does not have a transactivation domain. However, promoter assays showed that C/EBPβ-LIP and ATF4 synergistically transactivate the RANKL promoter. ChIP and IP assays revealed the cooperative binding of C/EBPβ and ATF4 on the RANKL promoter.
conclusionsWe demonstrated that C/EBPβ, especially C/EBPβ-LIP in cooperation with ATF4, is involved in osteoclast formation by regulating RANKL expression in RA-FLS. These findings suggest that C/EBPβ plays a crucial role in bone destruction in RA joints.
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