Matrix metalloproteinases and the regulation of tissue remodelling

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.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 collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . 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 molecules 3,4 . 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 § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs 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. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

Control of matrix metalloproteinase catalytic activity

“…Several reports in recent years have demonstrated that various MMPs act on non-matrix proteins, such as cytokines, chemokines, receptors, antimicrobial peptides, and more ). Thus, MMPs should not be viewed solely as proteinases of matrix catalysis, but rather as extracellular processing enzymes involved in regulating cell-cell and cell-matrix signaling events, quite typically, gain-of-function processing of latent proteins (Page-McCaw et al, 2007;Parks, 1999;Vu and Werb, 2000).…”

Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

“…The degradative functions of MMPs are critical in tissue remodeling, most notably in wound repair. 5 In addition to their enzymatic cleavage of matrix proteins, MMPs are able to activate cytokines, growth factors, and cell surface receptors, the last by limited proteolytic processing. 6 Based on their multiple biological activities, MMPs are thought to participate in a diverse range of pathological processes, including rheumatoid arthritis and fibrosis of the liver, kidneys, heart, and lungs.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…This review intends to discuss diverse functions of metalloproteinases implicated in cancer progression. Due to space constraints, we have chosen to concentrate our efforts on ADAMs and ADAMTSs, since MMPs have been extensively described in previous reviews [4][5][6][7][8][9]. Here, following a brief description of ADAMs and ADAMTSs, we explore their contribution to different steps of cancer progression.…”