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.