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.

TISSUE INHIBITOR OF METALLOPROTEINASE-3 IS UP-REGULATED BY TRANSFORMING GROWTH FACTOR-β1 IN VITRO AND EXPRESSED IN FIBROBLASTIC FOCI IN VIVO IN IDIOPATHIC PULMONARY FIBROSIS

“…Similar results have been reported in chondrocytes in which TGF-b also increased TIMP3 gene expression. Likewise, this up-regulation can also be blocked by genistein, suggesting partial similarities in the induction mechanisms [28]. Thus, these data strongly indicate that TGF-b-induced TIMP3 is mediated through phosphorylation on tyrosine residues.…”

The signaling mechanism of ROS in tumor progression

“…Alteration of the cellular environment through disease, injury, or exposure to pro-oxidants, or other insults can induce aberrant PKC activation leading to diseases such as cancer and diabetes [90]. Various PKC isozymes are well known to contribute to the progression of malignant phenotype [91] and serve as a key mediator for cell migration induced by a variety of cytokines [92,93]. PKC may cross-talk with integrinmediated signaling for cell spreading [94] and regulation of carcinoma cell chemotaxis [95].…”

Activation of PPARsα,β/δ, andγImpairs TGF-β1-Induced Collagens' Production and Modulat

“…In hyaline cartilage, TGF- β is produced in a latent form that does not activate TGF- β receptors but behaves as a great modulator of cartilage metabolism in its active form. Thus, it is a potent stimulator of chondrocyte proliferation [5] and differentiation [6] which stimulates cartilage-specific type II collagen or aggrecan synthesis [7–10] and modulates matrix metalloproteases activities by increasing synthesis of their natural tissue inhibitors [11, 12]. TGF- β 1 may have a multifaceted physiopathological role in joint diseases depending variably on cartilage protection, bone remodelling and synovial expression suggesting the involvement of TGF- β 1 in the evolution of osteoarthritis disease.…”