Bcl‐3 is an interleukin‐1–responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene

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Abstract
Objective: To define the role of Bcl‐3, a member of the inhibitor of nuclear factor κB (NF‐κB) family and a known regulator of NF‐κB, in interleukin‐1 (IL‐1)–induced matrix metalloproteinase 1 (MMP‐1) transcription in chondrocytes and synovial fibroblasts.Methods: SW‐1353 cells, a human chondrosarcoma cell line, were stimulated with IL‐1β, and the harvested RNA was subjected to microarray analysis and quantitative real‐time reverse transcription–polymerase chain reaction (RT‐PCR). The SW‐1353 cells were stimulated with IL‐1 or transfected with a plasmid that constitutively expressed Bcl‐3, and then MMP‐1 messenger RNA (mRNA) expression was assayed by quantitative real‐time RT‐PCR. SW‐1353 cells were transfected with antisense oligonucleotides to Bcl‐3, and IL‐1–induced MMP‐1 mRNA expression was assayed by quantitative RT‐PCR. SW‐1353 cells and rabbit synovial fibroblasts were transfected with a 4.3‐kb human MMP‐1 promoter construct along with Bcl‐3 and NF‐κB1 expression constructs, and MMP‐1 transcription was assayed.Results: Microarray analysis and real‐time RT‐PCR showed Bcl‐3 to be an IL‐1β–responsive gene in SW‐1353 cells. Exogenous expression of Bcl‐3 in SW‐1353 cells activated MMP‐1 transcription. Endogenous Bcl‐3 expression was required for IL‐1β induction of MMP‐1 gene expression. Bcl‐3 also activated MMP‐1 transcription in primary synovial fibroblasts. We showed previously that NF‐κB1 contributes to IL‐1β induction of MMP‐1 transcription in stromal cells. We showed here that Bcl‐3 can cooperate with NF‐κB1 to activate MMP‐1 transcription in SW‐1353 cells.Conclusion: These data define a new role for Bcl‐3 in joint cells as an IL‐1β–responsive early gene involved in cell‐mediated cartilage remodeling. Our findings implicate Bcl‐3 as an important contributor to chronic inflammatory disease states, such as osteoarthritis and rheumatoid arthritis.

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