Up-regulation of tissue inhibitor of metalloproteinases-3 gene expression by TGF-β in articular chondrocytes is mediated by serine/threonine and tyrosine kinases
✍ Scribed by Suming Su; John A. Dibattista; Yi Sun; Wen Qing Li; Muhammad Zafarullah
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 195 KB
- Volume
- 70
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
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-), 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--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-. Furthermore, two protein tyrosine kinase inhibitors, genistein and herbimycin A, inhibited TGF- induction of TIMP-3. H7 and genistein also suppressed TGF--induced TIMP-3 protein expression. These results suggest that TGF- signaling for TIMP-3 gene induction involves H7-sensitive serine/threonine kinase as well as herbimycin A-and genisteinsensitive protein tyrosine kinases.