Transcriptional regulation of ADAM-12 expression under normal and osteoarthritic conditions

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] ADAM 12 overexpression is linked to the pathology of diseases including osteoarthritis, cancer, cardiac hypertrophy, Alzheimers and multiple sclerosis. Degradation of fibrous cap and neo chondrogenesis are key events of OA. Several growth promoting agents including transforming growth factor-[beta] (TGF-[beta]) also play determining roles in the function of the cartilage specific cells. The potential link between growth factors and the pathogenesis of OA still remains unresolved. In the present study, we investigated TGF-[beta] mediated transcriptional induction of ADAM 12 in osteoblasts and synoviocytes, two of the resident cells of the joint. CAT assay revealed both positive and negative functioning elements at the proximal and the first exonic region of human ADAM 12 promoter. By using EMSA we showed increased interaction of NF[kappa]B, SAF-1 and Sp1 with the ADAM 12 promoter in TGF-[beta] stimulated cells. At the exonic region we also identified a highly conserved polydinucleotide repeat sequence that acts as a potent basal transcriptional repressor. These results suggest that the cohort action of NF[kappa]B, Sp1 and SAF-1 lead to the overexpression of ADAM 12 under osteoarthritic conditions.