Elsevier

Matrix Biology

Volume 19, Issue 7, December 2000, Pages 623-629
Matrix Biology

Mini review
Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases

https://doi.org/10.1016/S0945-053X(00)00102-5Get rights and content

Abstract

The matrix metalloproteinases (MMPs) can degrade a range of extracellular matrix proteins and have been implicated in connective tissue destruction and remodelling associated with cancer invasion and metastasis, cartilage destruction in arthritis, atherosclerotic plaque rupture, and the development of aneurysms. Recently, naturally occurring sequence variation has been detected in the promoter of a number of MMP genes. These genetic polymorphisms have been shown to have allele-specific effects on the transcriptional activities of MMP gene promoters, and to be associated with susceptibility to coronary heart disease, aneurysms and cancers. These findings indicate that variation in the MMP genes may contribute to inter-individual differences in susceptibility to these common, complex diseases, likely through effects on the balance between the synthesis and degradation of extracellular matrix proteins.

Introduction

At least 20 human matrix metalloproteinases (MMPs) have been identified (Table 1). In vitro studies have shown that the MMPs are capable of degrading a range of connective tissue proteins, indicating that these enzymes may play a role in connective tissue destruction and remodelling associated with various pathological processes, such as cancer invasion and metastasis, cartilage destruction in arthritis, atherosclerotic plaque rupture, and the development of aneurysms (Birkedal-Hansen et al., 1993, Murphy and Reynolds, 1993, Nagase and Woessner, 1999). Until recently, direct evidence has mostly come from ex vivo studies in which enhanced expression of MMPs can be detected in diseased tissues using RNA and protein analysis techniques such as in situ hybridisation, reverse transcriptase PCR, immunohistochemistry and zymography (Woessner, 1998). Over the last few years, however, other lines of evidence have also been accumulating. First, increased plasma/serum levels of certain MMPs have been reported in patients with cancer (Jung et al., 1997, Torii et al., 1997, Iizasa et al., 1999, Lein et al., 2000), rheumatoid arthritis (Zucker et al., 1994), osteoarthritis (Naito et al., 1999), systemic lupus erythematosus (Zucker et al., 1999a), multiple sclerosis (Lichtinghagen et al., 1999), polycystic kidney disease (Nakamura et al., 2000), abdominal aortic aneurysm (McMillan and Pearce, 1999), unstable angina (Kai et al., 1998) or acute myocardial infarction (Kai et al., 1998), likely due to seeping of MMP proteins from diseased tissues into the blood circulation (Zucker et al., 1999b). Second, studies of transgenic and gene knock-out animal models have demonstrated in vivo that MMP-3 can promote tumorigenesis (Sternlicht et al., 1999), and that MMP-3 as well as MMP-1 are involved in the process of dermal wound healing (Di Colandrea et al., 1998, Bullard et al., 1999).

Third, a number of naturally occurring variants of human MMP genes have been identified and found to be associated with susceptibility and/or progression of atherosclerosis, aneurysms and cancers, which is the subject of this brief overview.

Section snippets

Regulation of MMP expression and promoters of MMP genes

There are a number of regulatory mechanisms that can influence the ultimate impact of an MMP on extracellular matrix degradation. These at least include the following three most intensely studied mechanisms: regulation of transcription, activation of latent MMPs, and inhibition of MMP activity by tissue inhibitors of metalloproteinases (TIMPs). It appears, however, that for most MMPs, the key step is transcriptional regulation, because most MMP genes are expressed only when active physiological

Sequence variations in the human genome and their implications in disease susceptibility

DNA polymorphisms [naturally occurring DNA sequence changes with more than one variant (allele) having a frequency greater than 1% in a human population] have been estimated to occur on the average at one in every 1000 base pairs throughout the human genome (Sherry et al., 1999). Approximately 90% of DNA polymorphisms are single nucleotide polymorphisms (SNPs) due to single base substitutions (Collins et al., 1998). Some SNPs result in the generation or removal of a restriction endonuclease

Polymorphism in the MMP-3 (stromelysin-1) gene promoter

A polymorphism in the promoter of the MMP-3 gene was first reported in 1995 (Ye et al., 1995). The polymorphism is due to variation in the length of a polymonomeric track of adenosines located from position −1612 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In vitro promoter functional analyses showed that the 5A allele had greater promoter activities as compared with the 6A allele in fibroblasts

Polymorphisms in the MMP-9 (gelatinase B) gene promoter

A number of polymorphisms in the MMP-9 gene have been reported (St Jean et al., 1995, Zhang et al., 1999a), and two of them in the promoter of this gene have been shown to be functionally important. These are a (CA)n microsatellite polymorphism at position from −90 and a single nucleotide polymorphism at position −1562 (Peters et al., 1999, Shimajiri et al., 1999, Zhang et al., 1999b).

The multi-allelic microsatellite polymorphism has a bi-model distribution of allele frequencies, with the first

Polymorphism in the MMP-1 (collagenase-1) gene promoter

A polymorphism resulting from an insertion/deletion of a guanosine at position −1607 has been identified in the promoter of the MMP-1 gene (Rutter et al., 1998). Two alleles have been detected, one allele having a single gaunosine (1G) and the other having two guanosines (2G) at the polymorphic site. Promoter assays have indicated that this is also a functional polymorphism. The two guanosines (at positions −1607 and −1608) together with an adjacent adenosine create a core binding site

Polymorphism in the MMP-12 (metalloelastase) gene promoter

As discussed above, the cis-element AP-1 located at approximately 70 bp upstream from the transcriptional start site in a number of MMP genes plays a vital role in transcriptional regulation. Recently, a polymorphism was identified immediately adjacent to this AP-1 site in the MMP-12 gene (Jormsjo et al., 2000). The polymorphism, located at position −82, is due to an A to G substitution, with the A allele being more prevalent. In vitro studies have shown that this sequence change has an effect

Acknowledgements

The author would like to thank Professors Gillian Murphy and Dylan Edwards and Dr Ian Clark who kindly read this manuscript and provided valuable comments. Current research of the author is supported by the British Heart Foundation (PG/98183 and PG/98192).

References (58)

  • H. Nagase

    Stromelysins 1 and 2

  • H. Nagase et al.

    Matrix metalloproteinases

    J. Biol. Chem.

    (1999)
  • I. Nelissen et al.

    Polymorphism analysis suggests that the gelatinase B gene is not a susceptibility factor for multiple sclerosis

    J. Neuroimmunol.

    (2000)
  • S. Shimajiri et al.

    Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene

    FEBS Lett.

    (1999)
  • M.D. Sternlicht et al.

    The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis

    Cell

    (1999)
  • K.H. Weisgraber et al.

    Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine–arginine interchange at a single site

    J. Biol. Chem.

    (1982)
  • J.F. Woessner

    The matrix metalloproteinase family

  • S. Ye et al.

    Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression

    J. Biol. Chem.

    (1996)
  • S. Ye et al.

    Human stromelysin gene promoter activity is modulated by transcription factor ZBP-89

    FEBS Lett.

    (1999)
  • S. Yoon et al.

    Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms

    Biochem. Biophys. Res. Commun.

    (1999)
  • N. Zempo et al.

    Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery

    J. Vasc. Surg.

    (1994)
  • U. Benbow et al.

    Transcriptional repression of the human collagenase-1 (MMP-1) gene in MDA231 breast cancer cells by all-trans-retinoic acid requires distal regions of the promoter

    Br. J. Cancer

    (1999)
  • H. Birkedal-Hansen et al.

    Matrix metalloproteinases: a review

    Crit. Rev. Oral Biol. Med.

    (1993)
  • K.M. Bullard et al.

    Impaired wound contraction in stromelysin-1-deficient mice

    Ann. Surg.

    (1999)
  • M.J. Bullido et al.

    A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia

    Nat. Genet.

    (1998)
  • F.S. Collins et al.

    A DNA polymorphism discovery resource for research on human genetic variation

    Genome Res.

    (1998)
  • M.J. Davies

    Acute coronary thrombosis — the role of plaque disruption and its initiation and prevention

    Eur. Heart J.

    (1995)
  • M.E. Fini et al.

    Regulation of matrix metalloproteinase gene expression

  • Z.S. Galis et al.

    Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques

    J. Clin. Invest.

    (1994)
  • Cited by (0)

    View full text