Up‐regulation of tissue inhibitor of metalloproteinases‐3 gene expression by TGF‐β in articular chondrocytes is mediated by serine/threonine and tyrosine kinases

Abstract

The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulates extracellular matrix turn-over in normal animal development, cancer cell metastasis, atherosclerotic plaque rupture and erosion of arthritic cartilage. Transforming growth factor beta (TGF-beta), an inducer of matrix synthesis, potently enhances mRNA and protein of a recently characterized MMP inhibitor, TIMP-3, in bovine articular chondrocytes. We examined the implication of protein kinases in the TGF-beta-mediated induction of TIMP-3 expression by utilizing activators and inhibitors of these enzymes. Protein kinase A activators, dibutyryl cyclic AMP, or forskolin had little or no effect, respectively, while phorbol 12-myristate 13-acetate (PMA), a PKC activator, increased TIMP-3 gene expression. H7, a serine/threonine protein kinase inhibitor, markedly reduced the response of TIMP-3 gene to TGF-beta. Furthermore, two protein tyrosine kinase inhibitors, genistein and herbimycin A, inhibited TGF-beta induction of TIMP-3. H7 and genistein also suppressed TGF-beta-induced TIMP-3 protein expression. These results suggest that TGF-beta signaling for TIMP-3 gene induction involves H7-sensitive serine/threonine kinase as well as herbimycin A- and genistein-sensitive protein tyrosine kinases.

Cystatin C deficiency in human atherosclerosis and aortic aneurysms

“…However, the level of cystatin C mRNA was unchanged (Figure 4b), consistent with the constitutive nature of the cystatin C promoter (29). To explore further the regulation of cystatin C expression in SMC, we also tested a cytokine previously reported to induce other classes of protease inhibitors, TGF-β 1 (30)(31)(32). TGF-β 1 (5 ng/mL) did not change the level of cathepsin S mRNA or protein or of cystatin C mRNA (Figure 4b).…”

Fibroblast Activation Protein, a Dual Specificity Serine Protease Expressed in Reactive Human Tumor Stromal Fibroblasts

“…The MMPs are first synthesized as inactive zymogens that may be activated via cleavage of an activation propeptide by various membrane-type metalloproteases (MMPs) (43), by soluble MMPs that have already been activated (44), or via furin-dependent intracellular processing (45). MMPs are themselves transcriptionally regulated by various growth factors and cytokines (46,47). After activation, protein inhibitors known as the tissue inhibitors of metalloproteases (42) may inactivate the MMPs.…”

Differential Regulation of Extracellular Tissue Inhibitor of Metalloproteinases-3 Levels by Cell Membrane-bound and Shed Low Density Lipoprotein Receptor-related Protein 1

“…1). Thus, there is considerable interest in understanding factors regulating TIMP-3 levels, and it has been shown that transcription of TIMP-3 can be increased by the histone deacetylase SirT1 (10) and growth factors such as TGF␤ (11) and oncostatin M (12) and reduced by promoter methylation (13). Translation of TIMP-3 can be reduced by miR-21 (14), miR-221 and miR-222 (15), miR-181b (16), and miR-206 (17).…”