Zinc-Binding Protein-89 (ZBP-89) Cooperates with NF-kB to Regulate Expression of Matrix Metalloproteinases (MMPs) in Response to Inflammatory Cytokines

Matrix metalloproteinases (MMPs) have both protective and pathological roles in inflammation, and transcriptional mechanisms are important in regulating physiological levels to maintain health. Zinc-binding protein-89 (ZBP-89) is a transcription factor with roles in regulating vital cellular processes, acting through complex interactions with other proteins to ensure appropriate expression of tightly regulated genes. ZBP-89 binds the MMP-3 promoter at a polymorphic (5A/6A) site along with NF-kB. This polymorphism affects MMP-3 protein levels in tissues. In disease association studies, both over- and under-expression has negative consequences to health, and this promoter element is important in maintaining balanced expression. There is evidence that effects of the polymorphism vary under different conditions, but the role of ZBP-89 in these differences is not known. ZBP-89 was stably knocked-down in MG-63 osteosarcoma cells in order to study its role in regulation of MMP-3 expression in response to cytokines, and evaluate the functionality of a putative binding site in the MMP-1 promoter. Results show ZBP-89 is needed for maximal induction of both genes by IL-1ß and TNFα. Binding of both ZBP-89 and NF-kB to both promoters was decreased in the knock-down cells under basal and TNF-induced conditions, and protein interactions between ZBP-89 and NF-kB were suggested. These data provide the first evidence of a role for ZBP-89 in regulation of MMP-1 expression, and suggest the possibility of a larger role for ZBP-89 in inflammation through interactions with NF-kB.