DIFFERENTIAL-EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON THE EXPRESSION OF MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES IN YOUNG AND OLD HUMAN FIBROBLASTS

The balance between the activities of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) is an importa nt control point in tissue remodeling. Previous studies have demonstra ted elevated expression of the MMPs collagenase and stromelysin-l by a ged human diploid fibroblasts compared to early-passage cultures, We s how here that aging cells display an altered response to transforming growth factor-beta 1 (TGF beta 1) that selectively affects MMP mRNA ex pression. In both young and old cells, phorbol myristoyl-13 acetate (P MA) induced the expression of transcripts of collagenase, stromelysin- 1, gelatinase-B, TIMP-1, and TIMP-3. In young cells, TGF beta 1 recipr ocally modulated PMA-induced MMP and TIMP gene expression leading to r educed levels of transcripts for the MMPs and augmented accumulation o f TIMP-1 and TIMP-3 mRNAs, However, repressing effects of TGF beta 1 o n collagenase, stromelysin-1, and gelatinase-B RNA expression were not apparent in old cells, though induction of the TIMP genes was unimpai red. By electrophoretic mobility shift analysis the nuclear transcript ion factors AP1 and serum response factor (SRF) showed reduced levels of DNA binding activities in old fibroblasts compared to young cells. A probe for the TGF beta-inhibitory element (TIE) gave equivalent leve ls of complexes with nuclear extracts from both types of cells, though of different mobilities. We conclude that the effects of TGF beta 1 o n MMP and TIMP gene expression involve different cellular intermediari es, and suggest that altered composition or modification of TIE bindin g factors in aging cells may underlie the failure of TGF beta 1-mediat ed transcription repression. This mechanism may contribute to elevated constitutive expression of MMPs in old cells and to the connective ti ssue deterioration that accompanies the aging process.