• 1

    Nwomeh BC, Yager DR, Cohen IK: Physiology of the chronic wound. .Clin Plast Surg 25::341. ,1998. .

  • 2

    Suh DY, Hunt TK: Time line of wound healing. .Clin Podiatr Med Surg 15::1. ,1998. .

  • 3

    Nwomeh BC, Liang HX, Diegelmann RF, et al: Dynamics of the matrix metalloproteinases MMP-1 and MMP-8 in acute open human dermal wounds. .Wound Repair Regen 6::127. ,1998. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Nwomeh BC, Liang HX, Cohen IK, et al: MMP-8 is the predominant collagenase in healing wounds and nonhealing ulcers. .J Surg Res 81::189. ,1999. .

  • 5

    Woessner JF, Jr: The family of matrix metalloproteinases. .Ann N Y Acad Sci 732::11. ,1994. .

  • 6

    Gasparini G: The rationale and future potential of angiogenesis inhibitors in neoplasia. .Drugs 58::17. ,1999. .

  • 7

    Kugler A: Matrix metalloproteinases and their inhibitors. .Anticancer Res 19::1589. ,1999. .

  • 8

    Tortorella MD, Burn TC, Pratta MA, et al: Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins [comments]. .Science 284::1664. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Abbaszade I, Liu RQ, Yang F, et al: Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. .J Biol Chem 274::23443. ,1999. .

  • 10

    Rouis M, Adamy C, Duverger N, et al: Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice. .Circulation 100::533. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Moreau M, Brocheriou I, Petit L, et al: Interleukin-8 mediates downregulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages: relevance to stability of atherosclerotic plaque. .Circulation 99::420. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Shapiro SD: Elastolytic metalloproteinases produced by human mononuclear phagocytes: potential roles in destructive lung disease. .Am J Respir Crit Care Med 150::S160. ,1994. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Baramova E, Foidart JM: Matrix metalloproteinase family. .Cell Biol Int 19::239. ,1995. .

  • 14

    Birkedal-Hansen H: Proteolytic remodeling of extracellular matrix. .Curr Opin Cell Biol 7::728. ,1995. .

  • 15

    Borregaard N, Kjeldsen L, Lollike K, et al: Granules and vesicles of human neutrophils: the role of endomembranes as source of plasma membrane proteins. .Eur J Haematol 51::318. ,1993. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Yager DR, Zhang LY, Liang HX, et al: Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. .J Invest Dermatol 107::743. ,1996. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Young PK, Grinnell F: Metalloproteinase activation cascade after burn injury: a longitudinal analysis of the human wound environment. .J Invest Dermatol 103::660. ,1994. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Arumugam S, Jang YC, Chen-Jensen C, et al: Temporal activity of plasminogen activators and matrix metalloproteinases during cutaneous wound repair. .Surgery 125::587. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Agren MS: Gelatinase activity during wound healing. .Br J Dermatol 131::634. ,1994. .

  • 20

    Pilcher BK, Wang M, Qin XJ, et al: Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity. .Ann N Y Acad Sci 878::12. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Bullen EC, Longaker MT, Updike DL, et al: Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. .J Invest Dermatol 104::236. ,1995. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wysocki AB, Staiano-Coico L, Grinnell F: Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. .J Invest Dermatol 101::64. ,1993. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Agren MS, Jorgensen LN, Andersen M, et al: Matrix metalloproteinase 9 level predicts optimal collagen deposition during early wound repair in humans. .Br J Surg 85::68. ,1998. . [Erratum. Br J Surg 85: 715, 1998].

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Salo T, Makela M, Kylmaniemi M, et al: Expression of matrix metalloproteinase-2 and -9 during early human wound healing. .Lab Invest 70::176. ,1994. .

  • 25

    Makela M, Larjava H, Pirila E, et al: Matrix metalloproteinase 2 (gelatinase A) is related to migration of keratinocytes. .Exp Cell Res 251::67. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Murphy GJ, Murphy G, Reynolds JJ: The origin of matrix metalloproteinases and their familial relationships. .FEBS Lett 289::4. ,1991. .

  • 27

    Quantin B, Murphy G, Breathnach R: Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. .Biochemistry 28::5327. ,1989. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    McDonnell S, Matrisian LM: Stromelysin in tumor progression and metastasis. .Cancer Metastasis Rev 9::305. ,1990. .

  • 29

    Sires UI, Griffin GL, Broekelmann TJ, et al: Degradation of entactin by matrix metalloproteinases: susceptibility to matrilysin and identification of cleavage sites. .J Biol Chem 268::2069. ,1993. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Ueno H, Nakamura H, Inoue M, et al: Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas. .Cancer Res 57::2055. ,1997. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Takino T, Sato H, Shinagawa A, et al: Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library: MT-MMPs form a unique membrane-type subclass in the MMP family. .J Biol Chem 270::23013. ,1995. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Llano E, Pendas AM, Knauper V, et al: Identification and structural and functional characterization of human enamelysin (MMP-20). .Biochemistry 36::15101. ,1997. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Pendas AM, Knauper V, Puente XS, et al: Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. .J Biol Chem 272::4281. ,1997. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Bartlett JD, Simmer JP, Xue J, et al: Molecular cloning and mRNA tissue distribution of a novel matrix metalloproteinase isolated from porcine enamel organ. .Gene 183::123. ,1996. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Van Wart HE, Birkedal-Hansen H: The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. .Proc Natl Acad Sci USA 87::5578. ,1990. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Nagase H, Suzuki K, Enghild JJ, et al: Stepwise activation mechanisms of the precursors of matrix metalloproteinases 1 (tissue collagenase) and 3 (stromelysin). .Biomed Biochim Acta 50::749. ,1991. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Nagase H, Enghild JJ, Suzuki K, et al: Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4- aminophenyl) mercuric acetate. .Biochemistry 29::5783. ,1990. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Suzuki K, Enghild JJ, Morodomi T, et al: Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). .Biochemistry 29::10261. ,1990. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Suzuki K, Nagase H, Ito A, et al: The role of matrix metalloproteinase 3 in the stepwise activation of human rheumatoid synovial procollagenase. .Biol Chem Hoppe Seyler 371 (suppl)::305. ,1990. .

    • Search Google Scholar
    • Export Citation
  • 40

    Murphy G: Matrix metalloproteinases and their inhibitors. .Acta Orthop Scand Suppl 266::55. ,1995. .

  • 41

    Murphy G, Willenbrock F: Tissue inhibitors of matrix metalloendopeptidases. .Methods Enzymol 248::496. ,1995. .

  • 42

    Birkedal-Hansen H: Matrix metalloproteinases. .Adv Dent Res 9 (suppl 3)::16. ,1995. .

  • 43

    DeClerck YA, Yean TD, Lu HS, et al: Inhibition of autoproteolytic activation of interstitial procollagenase by recombinant metalloproteinase inhibitor MI/TIMP-2. .J Biol Chem 266::3893. ,1991. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Mauviel A: Cytokine regulation of metalloproteinase gene expression. .J Cell Biochem 53::288. ,1993. .

  • 45

    Kerr LD, Miller DB, Matrisian LM: TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence. .Cell 61::267. ,1990. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Mauviel A, Chung KY, Agarwal A, et al: Cell-specific induction of distinct oncogenes of the Jun family is responsible for differential regulation of collagenase gene expression by transforming growth factor-beta in fibroblasts and keratinocytes. .J Biol Chem 271::10917. ,1996. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Vincenti MP, Coon CI, Lee O, et al: Regulation of collagenase gene expression by IL-1 beta requires transcriptional and post-transcriptional mechanisms. .Nucleic Acids Res 22::4818. ,1994. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Harris IR, Yee KC, Walters CE, et al: Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. .Exp Dermatol 4::342. ,1995. .

  • 49

    Jude EB, Rogers AA, Oyibo SO, et al: Matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in diabetic and venous ulcers. .Diabetologia 44 (suppl 1)::3. ,2001. .

    • Search Google Scholar
    • Export Citation
  • 50

    Lobman R, Ambrosch A, Schultz G, et al: Expression of gelatinase (MMP-2) in diabetic and non-diabetic wounds. .Diabetologia 44 (suppl 1)::4. ,2001. .

    • Search Google Scholar
    • Export Citation
  • 51

    Trengove NJ, Stacey MC, MacAuley S, et al: Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. .Wound Repair Regen 7::442. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Edwards JV, Bopp AF, Batiste S, et al: Inhibition of elastase by a synthetic cotton-bound serine protease inhibitor: in vitro kinetics and inhibitor release. .Wound Repair Regen 7::106. ,1999. .

    • PubMed
    • Search Google Scholar
    • Export Citation

The Role of Matrix Metalloproteinases in Wound Healing

David G. Armstrong Director of Research and Education, Department of Surgery, Southern Arizona Veterans Affairs Medical Center, Tucson, AZ; Visiting Senior Lecturer of Medicine, Department of Medicine, Manchester Royal Infirmary, Manchester, UK. Mailing address:Department of Surgery, 3601 S Sixth Ave, Tucson, AZ 85723.

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Edward B. Jude University Department of Medicine, Manchester Royal Infirmary, Manchester, UK.

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The structure, classification, function, and regulation of matrix metalloproteinases in normal and abnormal wound healing is discussed. Results from key studies suggest that neutrophil-derived matrix metalloproteinase 8 (MMP-8) is the predominant collagenase present in normal healing wounds, and that overexpression and activation of this collagenase may be involved in the pathogenesis of nonhealing chronic leg ulcers. Excessive collagenolytic activity in these chronic wounds is possible because of the reduced levels of tissue inhibitor metalloproteinase 1 (TIMP-1). However, until recently, there have been no studies evaluating levels of matrix metalloproteinase or tissue inhibitors of metalloproteinase activity in chronic diabetic foot wounds. Improving basic knowledge and pharmaceutical intervention in this area ultimately may help clinicians identify and proactively intervene in an effort to prevent normal wounds from becoming chronic. This may prevent the high prevalence of morbidity associated with this significant health problem. (J Am Podiatr Med Assoc 92(1): 12-18, 2002)