Transforming Growth Factor-β Induces Collagenase-3 Expression by Human Gingival Fibroblasts via p38 Mitogen-activated Protein Kinase

Abstract

Controlled degradation of extracellular matrix (ECM)1 is essential in physiological situations involving connective tissue remodeling, such as tissue morphogenesis, repair, and angiogenesis. On the other hand, excessive breakdown of connective tissue components plays an important role in destruction of functional tissue architecture, e.g. in rheumatoid arthritis, osteoarthritis, atherosclerosis, periodontitis, autoimmune blistering disorders of skin, and dermal photoaging as well as in invasion and metastasis of tumor cells (see Refs. 1-3). Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases collectively capable of degrading essentially all ECM components, and they are implicated in ECM remodeling in the physiologic and pathologic situations mentioned above. At present, 18 human members of the MMP family have been characterized, and most of them can be divided into subgroups of collagenases, gelatinases, stromelysins, and membrane-type MMPs based on their substrate specificity and structure (1-3).Collagenase-1 (MMP-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13) are the principal neutral proteinases capable of degrading native fibrillar collagens in the extracellular space. They all cleave type I, II, and III collagens at a specific site, generating 3 ⁄4 N-terminal and 1 ⁄4 C-terminal fragments, which denature in physiological temperature and are further degraded by other MMPs, e.g. gelatinases (see Refs. 1-3). MMP-13 also cleaves type I collagen at N-terminal nonhelical telopeptide (4). MMP-1 cleaves type III collagen and MMP-8 type I collagen most effectively (1-3). MMP-13, in turn, cleaves fibrillar collagens with preference to type II collagen over type I and III collagens and displays 40-fold stronger gelatinase activity than MMP-1 and MMP-8 (5-7). In addition, MMP-13 degrades type IV, X, and XIV collagens, tenascin, fibronectin, and aggrecan core protein (8 -9). Apparently due to its exceptionally wide substrate specificity, the physiologic expression of MMP-13 is limited to situations in which rapid and effective remodeling of collagenous ECM takes place, i.e. fetal bone development and adult bone remodeling (10, 11). On the other hand, MMP-13 is expressed at sites of excessive degradation of

Connective Tissue Metabolism and Gingival Overgrowth

“…MMP-13 is a collagenase with wide substrate specificity, whereas MMP-1 is a collagenase more restricted to hydrolyzing fibrillar collagens. Differential regulation of these two MMP genes is likely to be of biological importance, and may be related to the generally lower tendency for scar formation in oral tissues (Ravanti et al, 1999). In addition, integrin expression patterns differ between gingival fibroblasts and dermal fibroblasts, whereas periodontal ligament fibroblasts and gingival fibroblasts are more similar to each other in this respect (Palaiologou et al, 2001).…”

“…In contrast, MMP-1 is predominantly expressed in adult dermal wounds. Moreover, MMP-13 is strongly up-regulated by TGF-␤1 in human gingival fibroblasts, but is down-regulated in human dermal fibroblasts grown under the same conditions (Ravanti et al, 1999;Leivonen et al, 2002). MMP-13 is a collagenase with wide substrate specificity, whereas MMP-1 is a collagenase more restricted to hydrolyzing fibrillar collagens.…”

Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells

“…Collagenases are the principal proteinases capable of cleaving native fibrillar collagens (Ala-aho and Ka¨ha¨ri, 2005). Collagenase-3 (MMP-13) has a notably wide substrate specificity, and its expression is limited to physiologic situations, in which rapid and effective remodeling of collagenous ECM is required, for example fetal development of bone, postnatal bone remodeling, and gingival and fetal skin wound repair (Johansson et al, 1997b;Sta˚hle-Ba¨ckdahl et al, 1997;Ravanti et al, 1999Ravanti et al, , 2001). However, the wide substrate specifity of MMP-13 suggests that it is also a powerful invasion tool for cancer cells.…”

Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis

“…Studies have shown an involvement of p38 kinase activity in TGF-b induced several MMP biosynthesis in fibroblasts, breast epithelial cells or in transformed keratinocytes (Ravanti et al, 1999;Johansson et al, 2000;Kim et al, 2004Kim et al, , 2005.…”