Because of the therapeutic implications, inhibiting MMP-1 has been a major focus of research. Reducing MMP-1 levels could prevent the irreversible degradation of cartilage, tendon, and bone in arthritis and impede the process of tumor migration and invasion in cancer. Considerable attention has, therefore, been directed at the inhibition of collagenase activity, with either naturally occurring protein inhibitors (the TIMPs) or with synthetic compounds. Alternatively, inhibition of MMP-1 can occur by inhibiting the synthesis of this enzyme. The focus of this section is a discussion of mechanisms that inhibit the synthesis of MMP-1 at the transcriptional level.
Transforming growth factor p (TGF- p), and the vitamin A derivatives, all-trans-retinoic acid and the synthetic retinoids, suppress the transcription of MMP-1.111-112 TGF- p mediates its effect through a TGF- p inhibitory element (TIE 5'-GAGTTGGTGA-3'), which is located at -709 bp of the rat stromelysin-1 promoter.113 Interestingly, these authors show that c-Fos binding is necessary for the inhibitory effects on transcription. The presence of this site has been described in the rabbit114 and human113 MMP-1 promoters located at -249 bp and at -245 bp, respectively. Due to the similarity in both sequences (rabbit: 5'-GAAATGGAGA-3'; human: 5'-GAATTGGAGA-3', a 2 to 3 bp difference from the originally described TIE in the stromelysin-1 gene) and the conserved location of this element in the two MMP-1 promoters, it is possible that it is functional. Indeed, in the rabbit promoter, this element also binds c-Fos. Moreover, mutations in this element result in a significant increase in both basal and TPA-induced transcription in fibroblasts, suggesting that the TIE may have a novel role as a constitutive repressor of the MMP-1 gene in these cells.114
Considerable attention has been focused on the mechanism(s) by which retinoids inhibit MMP-1 transcription.112 Retinoids mediate their effects through one family of the nuclear hormone receptors: the retinoic acid and retinoid X receptors (RARs and RXRs, respectively).115-116 Both RARs and RXRs have an a, p, and y subtype and their functional activity depends on their ability to form RXR/RXR homodimers, or RAR/RXR heterodimers. These dimers can then either bind to the DNA directly, via retinoic acid response elements (RAREs), or indirectly to other sites in the DNA. The formation and precise effect of either the RXR homodimer or the RXR/RAR heterodimer is most likely dependent on the ligand availability and receptor concentration within the cell type.117
The MMP-1 promoter does not contain an RARE, and it has been demonstrated that in fibroblasts, RARs/RXRs suppress transcription of MMP-1 by interacting with the proximal AP-1 site via protein-protein interactions.118-121 Other studies suggest that alternative mechanisms contribute to suppression of MMP-1 by retinoids. These include 1) a conformational change in the DNA resulting from the association of the RARs/RXRs with AP-1 proteins bound to the DNA, with a subsequent inhibition of transcription; 2) the interaction of RARs/RXRs with corepressors, which downregulate transcription;122 3) the interference of RARs/RXRs with the transcriptional machinery, since the -77 bp AP-1 site is in close proximity to the preinitiation complex;123 4) the sequestration of c-Jun by the RARs/RXRs prevents them from binding to the promoter and trans-activating the gene;118-122,124,125 or 5) PEA3/protein interactions (see below). It is possible that multiple mechanisms may be operational simultaneously, a concept that emphasizes both the redundancy in the pathways regulating transcription and the importance of precise control of MMP-1 gene expression.
Recently, novel mechanisms of MMP-1 repression have been reported. Schneikert et al126 have shown that the androgen receptor directly interacts with a PEA3/Ets-related protein, ERM, resulting in the inhibition of MMP-1. In addition, Benbow et al127 have demonstrated that a PEA3 site at -3108 bp constitutively binds RAR/RXR proteins, probably via protein-protein interactions. Despite this constitutive binding, however, repression of MMP-1 transcription occurs only in the presence of ligand. Possibly, the addition of retinoic acid triggers a conformational change in the RAR/RXR proteins,121,127,128 or a post-translational event, such as phosphorylation, that culminates in the repression of transcription.129 There is also evidence that the repression by the nuclear hormone receptors occurs in a ligand-independent manner, in which the receptors become translocated to the nucleus by nonhormonal stimuli, such as heat shock. Interestingly, this suggests that the receptors can repress transcription even under conditions where hormone is absent.112
It is already well accepted that retinoids have potent antiproliferative effects,117 and much effort has been directed towards developing their therapeutic potential in cancer. Since these compounds also suppress MMP-1 synthesis, it is equally possible that they may have an additional role in suppressing the process of tumor invasion and metastasis, by suppressing the transcription of MMP-1. Since tumor cells can contribute to their own invasiveness130 and some tumor cells constitutively express MMP-1,15,64 the concept that decreasing MMP-1 may decrease the invasive potential of certain tumor cells is intriguing. Understanding the molecular mechanisms behind this suppression may be a goal of future studies and, eventually, form the basis for therapeutic intervention.
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