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  • Review Article
  • Published:

Matrix metalloproteinases and the regulation of tissue remodelling

Nature Reviews Molecular Cell Biology volume 8, pages 221–233 (2007)Cite this article

Key Points

  • Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease.

  • Recent work has highlighted the diverse consequences of MMP proteolysis on normal and pathological cell behaviour.

  • Mutations in mouse MMP genes have displayed phenotypes in normal skeletal, mammary and vascular development.

  • Drosophila melanogaster has only two MMP genes; mutations in both MMP genes have been isolated. Each mutant is larval lethal with defects in tissue remodelling.

  • Collectively, the loss-of-function studies in different organisms point to MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or associated with disease.

  • An important outstanding question is whether MMPs function primarily as structural effectors of tissue remodelling or as regulators of signalling networks.

  • In this Review, we synthesize the current genetic evidence from mice, flies and humans on the normal functions of MMPs in embryonic and postnatal development. We highlight the consequences of modifying MMP action in D. melanogaster larval development, mammalian skeletal, vascular and mammary development and in inflammation and wound repair.

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.

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Figure 1: Schematic structure of MMPs.
Figure 2: Possible modes of MMP action.
Figure 3: Skeletal phenotypes of MMP mutants.
Figure 4: Mammary gland phenotypes of MMP mutants.
Figure 5: Phenotypes of Drosophila melanogaster DmMmp1 and DmMmp2 mutant flies.

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Acknowledgements

This study was supported by grants from the National Institutes of Health (NIH) to Z.W. and to A.P.-M and a March of Dimes Basil O'Connor award to A.P.-M. A.J.E. was supported by an NIH National Research Service Award Institutional Fellowship and by the California Breast Cancer Research Program. We apologize to the many scientists whose papers we were unable to cite owing to space constraints.

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  1. Andrea Page-McCaw and Andrew J. Ewald: These authors contributed equally to this paper.

Authors and Affiliations

  1. Department of Biology and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, 12180, New York, USA

    Andrea Page-McCaw

  2. Department of Anatomy and Program in Biomedical Sciences, University of California, San Francisco, 94143-0452, California, USA

    Andrew J. Ewald & Zena Werb

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MEROPS

Glossary

Fibrillar collagen

Polymerized, supramolecular collagen that has been organized into fibrils; collagen types I, II and III form fibrils.

Extracellular matrix

Complex, ordered mixture of structural and signalling molecules that surrounds cells.

Enzymatic redundancy

Two enzymes that are expressed in the same time and place that can fully substitute for each other's essential functions.

Enzymatic compensation

Upregulation of an enzyme, which is normally not expressed (or is expressed at a low level) to substitute for the absence of a mutated enzyme.

Adaptive development

Alternative developmental trajectory whereby an organism compensates for the loss of a gene by doing some essential function in a reproducibly different manner.

Catalytic domain

A domain that cleaves other proteins.

Pro-domain

An autoinhibitory domain that prevents the catalytic domain from functioning.

Hemopexin domain

A four-bladed β-propeller domain that mediates protein–protein interactions.

Tissue inhibitor of metalloproteinases

(TIMPs). Endogenous protein inhibitors of matrix metalloproteinase function.

Intramembranous ossification

Direct differentiation of mesenchymal precursors into osteoblasts, as in the clavicle and in some skull bones.

Endochondral ossification

Bone development in which a cartilage template forms first and is then replaced by mineralized bone in the growth plate, as in the long bones.

Pseudo-metamorphic ossification

Bone development in which a cartilage template functions as a temporary mould to shape the deposition of bone, as in the mandible.

Osteoblast

A cell that secretes unmineralized type-I-collagen-rich extracellular matrix and builds bone.

Growth plate

The region of developing appendicular and axial skeleton that is responsible for growth in length of bones.

Aggrecan

The main chondroitin sulphate proteoglycan in cartilage.

Trabeculae

A fine network of bony spicules in trabecular bone.

Osteoclast

A cell that resorbs the mineralized matrix of the bone.

Terminal end bud

A highly proliferative epithelial structure at the end of invading mammary ductal epithelium during puberty.

Secondary branching

Also known as side branching. A process during mammary development whereby secondary ducts initiate laterally off of main ducts during puberty.

Corneal angiogenesis assay

Stimulated neovascularization assay in which test substances are implanted in the cornea of a rabbit or mouse and the cornea is monitored for the development of new blood vessels.

Perivascular cells

Also known as pericytes, mural cells or smooth muscle cells. These cells are tightly associated with endothelial cells and aid in the function and regulation of vascular networks.

Endothelial cells

Cells that constitute the lining of the blood vessels.

MMP degradome

The complete list of matrix metalloproteinase proteolytic substrates.

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Page-McCaw, A., Ewald, A. & Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8, 221–233 (2007). https://doi.org/10.1038/nrm2125

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