Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms

Agents like retinoids, thyroid hormone, glucocorticoids, progesterone, androgens, which bind to members of the nuclear receptor superfamily, inhibit the synthesis of matrix metalloproteinases (MMPs) in many cell types. These Zn2(+)- and Ca2(+)-dependent MMPs degrade components of the extracellular matrix (ECM), and precise regulation of their expression is crucial in many normal processes. However, inappropriate expression of MMPs contributes to a variety of invasive and erosive diseases, and inhibition of MMP synthesis provides an important mechanism for controlling such aberrant or dysregulated responses. Nuclear receptors control MMPs through a variety of seemingly redundant mechanisms. First, nuclear receptors act on the promoters of MMP genes to enhance or suppress trans-activation. Ironically, in a family of genes that exhibits substantial regulation by nuclear receptors, few consensus hormone responsive elements (HREs) have been deomonstrated in MMP promoters. Rather, inhibition of MMPs occurs primarily, but not exclusively, at AP-1 sites. Here, nuclear receptors form complexes on the DNA through interactions with AP-1 proteins, sequester Fos/Jun and/or decrease the mRNAs for these transcription factors. Second, nuclear receptors and their ligands can indirectly inhibit MMPs. For instance, both retinoids and glucocorticoids induce the transcription of TIMPs (tissue inhibitor of metalloproteinases), which complex with MMPs and inhibit enzymatic activity, and progesterone stimulates production of transforming growth factor-beta (TGF-beta), which in turn suppresses MMP-7 (matrilysin). Finally, nuclear receptors bind to coactivators, corepressors, and components of the general transcriptional apparatus, but the potential role of these interactions in MMP regulation remains to be determined. We conclude that nuclear receptors utilize multiple, apparently redundant, mechanisms to inhibit MMP gene expression, assuring precise control of ECM degradation under a variety of physiologic and pathologic conditions.