Nat Rev Mol Cell Biol 8(3): 221-233

Matrix metalloproteinases and the regulation of tissue remodelling

^{Department of Biology and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA}

^{Department of Anatomy and Program in Biomedical Sciences, University of California, San Francisco, California 94143-0452, USA}

Andrea Page-McCaw: ude.ipr@amegap; Andrew J. Ewald: ude.fscu@dlawe.werdna; Zena Werb: ude.fscu@brew.anez

^{These authors contributed equally to this paper.}

Andrea Page-McCaw: ude.ipr@amegap; Andrew J. Ewald: ude.fscu@dlawe.werdna; Zena Werb: ude.fscu@brew.anez

Abstract

Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.

Abstract

The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen¹2. Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium³. In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules³4. Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.

Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5). However, recent clinical data indicate that the relationship between MMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. Surely we do not have 23 MMPs in our bodies just to promote tumours. A main question remains unanswered: what is the normal function of the MMP gene family in development? This Review focuses on what we have learned about the normal in vivo functions of MMPs from genetic analysis.

Footnotes

Competing interests statement

The authors declare no competing financial interests.

DATABASES

The following terms in this article are linked online to:

Entrez Genome:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

DmMmp1 | DmMmp2

UniProtKB:http://ca.expasy.org/sprot

MMP1 | MMP2 | MMP3 | MMP9 | MMP14 | MMP15 | MMP16 | MMP17 | MMP23 | MMP24 | MMP25

FURTHER INFORMATION

Andrea Page-McCaw's homepage:www.rpi.edu/research/biotech/researchers/page-mccaw.html

Zena Werb's homepage:http://anatomy.ucsf.edu/Pages/werb.html

International Proteolysis Society:hhttp://www.protease.org

MEROPS:http://merops.sanger.ac.uk

Footnotes

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