Nuclear factor binding to an AP-1 site is associated with the activation of pro-alpha 1(I)-collagen gene in dedifferentiating chondrocytes.

Isolated chondrocytes grown on plastic gradually lose their differentiated phenotype upon subculturing. This dedifferentiation is manifested by an altered production of extracellular-matrix molecules (ECM): e.g., the cartilage specific type II collagen is replaced by types I and III. We have studied the regulation of ECM gene expression in dedifferentiating human and murine fetal chondrocytes. Nuclear extracts from dedifferentiated cells, human fetal fibroblasts and 3T3 cells contained a protein that bound in an electrophoretic mobility shift assay to an AP-1 site in the first intron of the human alpha 1(I) collagen gene. This binding activity was not present in freshly isolated human or murine chondrocytes, which produced type II, but not type I, collagen mRNA in culture. Thus the binding activity was induced simultaneously with alpha 1(I)-collagen-gene expression during dedifferentiation. The specific interaction was sensitive to dephosphorylation of the nuclear extract and to chemical modification of reduced cysteine residues. The AP-1 site we studied had previously been shown to be a positive transcriptional contributor in the first intron to the expression of the alpha 1(I) collagen gene. In transient transfections into dedifferentiating chondrocytes, an alpha 1(I) collagen expression plasmid carrying a mutated AP-1 site in the first intron resulted in three-times-lower reporter gene RNA levels than a plasmid carrying the respective functional AP-1 site. These data suggest that the AP-1 sequence and its respective trans-acting factors may play a role in the transcriptional regulation of the alpha 1(I) collagen gene during dedifferentiation of chondrocytes.

Comparison between lovastatin and gemfibrozil in the treatment of primary hypercholesterolemia: the Finnish Multicenter Study.

A randomized, double-blind 12-week comparison of lovastatin and gemfibrozil in the treatment of patients with primary hypercholesterolemia with normal or moderately elevated triglycerides was performed in 334 patients from 19 centers in Finland. Patients with "high" total serum cholesterol (240 to 300 mg/dl) constituted Stratum 1 and patients with "very high" total serum cholesterol (greater than 300 mg/dl) constituted Stratum 2. In Stratum 1, patients were randomly assigned to either lovastatin 20 mg nightly or gemfibrozil 600 mg twice daily, and in Stratum 2 to either lovastatin 40 mg nightly or gemfibrozil 600 mg twice daily. In both strata, the lovastatin dose was doubled after 6 weeks if serum cholesterol remained greater than 200 mg/dl. Ninety-two and 93% of the patients doubled their dose in Strata 1 and 2, respectively, resulting in average doses of 38.5 mg/day (Stratum 1) and 77.4 mg/day (Stratum 1) and 77.4 mg/day (Stratum 2) by week 12. The dose of gemifibrozil was kept constant. Lovastatin reduced low-density lipoprotein (LDL) cholesterol by 31 and 42% in Stratum 1 and 2, respectively. The corresponding reductions achieved by gemfibrozil were 13 and 18%. In both strata, as well as in patients with Type IIa and IIb hyperlipoproteinemia, lovastatin was approximately 2 to 4 times as effective as gemfibrozil in lowering LDL cholesterol. Although both drugs increased high-density lipoprotein (HDL) cholesterol concentrations, gemfibrozil was 1.5 to 3 times more effective. LDL/HDL cholesterol ratios decreased significantly more during lovastatin therapy. Both drugs reduced serum triglyceride levels, but gemfibrozil was much more effective.(ABSTRACT TRUNCATED AT 250 WORDS)