CoChat
Sign Up
Cited by 173Wound Healing and TreatmentsProtease and Inhibitor MechanismsLiver physiology and pathology

Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis

Open access
Kyriakides, Themis R., Wulsin, Drausin, Skokos, Eleni A., Fleckman, Philip, Pirrone, Annalisa, Shipley, J. Michael, Senior, Robert M., Bornstein, Paul·2009·Matrix Biology
DOI 10.1016/j.matbio.2009.01.001PMC PMC2673333
Open this paper in CoChat — free account

Abstract

Matrix metalloproteinase- (MMP-9) is involved in processes that occur during cutaneous wound healing such as inflammation, matrix remodeling, and epithelialization, To investigate its role in healing, full thickness skin wounds were made in the dorsal region of MMP-9-null and control mice and harvested up to 14 days post wounding. Gross examination and histological and immunohistochemical analysis indicated delayed healing in MMP-9-null mice. Specifically, MMP-9-null wounds displayed compromised reepithelialization and reduced clearance of fibrin clots. In addition, they exhibited abnormal matrix deposition, as evidenced by the irregular alignment of immature collagen fibers. Despite the presence of matrix abnormalities, MMP-9-null wounds displayed normal tensile strength. Ultrastructural analysis of wounds revealed the presence of large collagen fibrils, some with irregular shape. Keratinocyte proliferation, inflammation, and angiogenesis were found to be normal in MMP-9-null wounds. In addition, VEGF levels were similar in control and MMP-9-null wound extracts. To investigate the importance of MMP-9 in wound reepithelialization we tested human and murine keratinocytes in a wound migration assay and found that antibody-based blockade of MMP-9 function or MMP-9 deficiency retarded migration. Collectively, our observations reveal defective healing in MMP-9-null mice and suggest that MMP-9 is required for normal progression of wound closure.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.matbio.2009.01.001

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Lower levels of active MMP9, especially reduction at day 7, correlate with delayed reepithelization and disorderly collagen fibrillogenesis in THS-exposed mice.

    “Furthermore, lower levels of active MMP9, especially the reduction at day 7, correlate with delayed reepithelization and disorderly collagen fibrillogenesis [14,43].”

    From Tobacco toxins deposited on surfaces (third hand smoke) impair wound healing (2016) · cites this paper as [43]

    The Results report delayed reepithelialization and irregularly organized collagen fibers in MMP-9-null mouse wounds. The cited paper studies mice lacking MMP-9, not THS-exposed mice, and the supplied passages do not establish a reduction in active MMP-9 specifically at day 7. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 39

  1. Agah A Kyriakides TR Lawler J Bornstein P 2002 The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice Am J Pathol 161 831 839 12213711 PMC1867266
  2. Agah A Kyriakides TR Letrondo N Bjorkblom B Bornstein P 2004 Thrombospondin 2 levels are increased in aged mice: consequences for cutaneous wound healing and angiogenesis Matrix Biol 22 539 547 14996433
  3. Agren MS Mirastschijski U Karlsmark T Saarialho-Kere UK 2001 Topical synthetic inhibitor of matrix metalloproteinases delays epidermal regeneration of human wounds Exp Dermatol 10 337 348 11589731
  4. Belotti D Paganoni P Manenti L Garofalo A Marchini S Taraboletti G Giavazzi R 2003 Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation Cancer Res 63 5224 5229 14500349
  5. Bornstein P Kyriakides TR Yang Z Armstrong LC Birk DE 2000 Thrombospondin 2 modulates collagen fibrillogenesis and angiogenesis J Investig Dermatol Symp Proc 5 61 66 11147677
  6. Bradshaw AD Puolakkainen P Dasgupta J Davidson JM Wight TN Helene Sage E 2003 SPARC-null mice display abnormalities in the dermis characterized by decreased collagen fibril diameter and reduced tensile strength J Invest Dermatol 120 949 955 12787119
  7. Brown LF Yeo KT Berse B Yeo TK Senger DR Dvorak HF van de Water L 1992 Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing J Exp Med 176 1375 1379 1402682 PMC2119412
  8. Christiansen DL Huang EK Silver FH 2000 Assembly of type I collagen: fusion of fibril subunits and the influence of fibril diameter on mechanical properties Matrix Biol 19 409 420 10980417
  9. Eming SA Krieg T Davidson JM 2007 Inflammation in wound repair: molecular and cellular mechanisms J Invest Dermatol 127 514 525 17299434
  10. Fleckman P Holbrook KA Dale BA Sybert VP 1987 Keratinocytes cultured from subjects with ichthyosis vulgaris are phenotypically abnormal J Invest Dermatol 88 640 645 2437218
  11. Goldfinger LE Stack MS Jones JC 1998 Processing of laminin-5 and its functional consequences: role of plasmin and tissue-type plasminogen activator J Cell Biol 141 255 265 9531563 PMC2132728
  12. Gurtner GC Werner S Barrandon Y Longaker MT 2008 Wound repair and regeneration Nature 453 314 321 18480812
  13. Hitomi K Presland RB Nakayama T Fleckman P Dale BA Maki M 2003 Analysis of epidermal-type transglutaminase (transglutaminase 3) in human stratified epithelia and cultured keratinocytes using monoclonal antibodies Journal of dermatological science 32 95 103 12850301
  14. Kirfel G Herzog V 2004 Migration of epidermal keratinocytes: mechanisms, regulation, and biological significance Protoplasma 223 67 78 15221512
  15. Kobayashi T Kishimoto J Ge Y Jin W Hudson DL Ouahes N Ehama R Shinkai H Burgeson RE 2001 A novel mechanism of matrix metalloproteinase-9 gene expression implies a role for keratinization EMBO reports 2 604 608 11463743 PMC1083943
  16. Krady MM Zeng J Yu J Maclauchlan S Skokos EA Tian W Bornstein P Sessa WC Kyriakides TR 2008 Thrombospondin-2 Modulates Extracellular Matrix Remodeling during Physiological Angiogenesis Am J Pathol 173 879 891 18688033 PMC2527070
  17. Kyriakides TR Tam JW Bornstein P 1999 Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene J Invest Dermatol 113 782 787 10571734
  18. Kyriakides TR Zhu YH Yang Z Huynh G Bornstein P 2001 Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice Am J Pathol 159 1255 1262 11583953 PMC1850515
  19. Lavagnino M Arnoczky SP Frank K Tian T 2005 Collagen fibril diameter distribution does not reflect changes in the mechanical properties of in vitro stress-deprived tendons Journal of biomechanics 38 69 75 15519341
  20. Lee S Jilani SM Nikolova GV Carpizo D Iruela-Arispe ML 2005 Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors J Cell Biol 169 681 691 15911882 PMC2171712
  21. Lindsey ML Escobar GP Dobrucki LW Goshorn DK Bouges S Mingoia JT McClister DM Jr Su H Gannon J MacGillivray C Lee RT Sinusas AJ Spinale FG 2006 Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction American journal of physiology 290 H232 239 16126817
  22. Mirastschijski U Haaksma CJ Tomasek JJ Agren MS 2004 Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds Exp Cell Res 299 465 475 15350544
  23. Mohan R Chintala SK Jung JC Villar WV McCabe F Russo LA Lee Y McCarthy BE Wollenberg KR Jester JV Wang M Welgus HG Shipley JM Senior RM Fini ME 2002 Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration J Biol Chem 277 2065 2072 11689563
  24. Page-McCaw A Ewald AJ Werb Z 2007 Matrix metalloproteinases and the regulation of tissue remodelling Nat Rev Mol Cell Biol 8 221 233 17318226 PMC2760082
  25. Pilcher BK Dumin JA Sudbeck BD Krane SM Welgus HG Parks WC 1997 The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix J Cell Biol 137 1445 1457 9182674 PMC2132537
  26. Pirrone A Hager B Fleckman P 2005 Primary mouse keratinocyte culture Methods in molecular biology Clifton, N.J 289 3 14 15502164
  27. Raja Sivamani K Garcia MS Isseroff RR 2007 Wound re-epithelialization: modulating keratinocyte migration in wound healing Front Biosci 12 2849 2868 17485264
  28. Santoro MM Gaudino G 2005 Cellular and molecular facets of keratinocyte reepithelization during wound healing Exp Cell Res 304 274 286 15707592
  29. Singer AJ Clark RA 1999 Cutaneous wound healing N Engl J Med 341 738 746 10471461
  30. Sternlicht MD Werb Z 2001 How matrix metalloproteinases regulate cell behavior Annu Rev Cell Dev Biol 17 463 516 11687497 PMC2792593
  31. Sung HJ Johnson CE Lessner SM Magid R Drury DN Galis ZS 2005 Matrix metalloproteinase 9 facilitates collagen remodeling and angiogenesis for vascular constructs Tissue engineering 11 267 276 15738681
  32. Thomas GJ Poomsawat S Lewis MP Hart IR Speight PM Marshall JF 2001 alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes J Invest Dermatol 116 898 904 11407978
  33. Visscher DW Hoyhtya M Ottosen SK Liang CM Sarkar FH Crissman JD Fridman R 1994 Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence International journal of cancer 59 339 344 7927938
  34. Vu TH Shipley JM Bergers G Berger JE Helms JA Hanahan D Shapiro SD Senior RM Werb Z 1998 MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes Cell 93 411 422 9590175 PMC2839071
  35. Wang X Jung J Asahi M Chwang W Russo L Moskowitz MA Dixon CE Fini ME Lo EH 2000 Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury J Neurosci 20 7037 7042 10995849 PMC6772824
  36. White JF Werkmeister JA Darby IA Bisucci T Birk DE Ramshaw JA 2002 Collagen fibril formation in a wound healing model Journal of structural biology 137 23 30 12064930
  37. Wilgus TA Matthies AM Radek KA Dovi JV Burns AL Shankar R DiPietro LA 2005 Novel function for vascular endothelial growth factor receptor-1 on epidermal keratinocytes Am J Pathol 167 1257 1266 16251410 PMC1603795
  38. Wu N Jansen ED Davidson JM 2003 Comparison of mouse matrix metalloproteinase 13 expression in free-electron laser and scalpel incisions during wound healing J Invest Dermatol 121 926 932 14632214
  39. Xue M Jackson CJ 2008 Autocrine Actions of Matrix Metalloproteinase (MMP)-2 Counter the Effects of MMP-9 to Promote Survival and Prevent Terminal Differentiation of Cultured Human Keratinocytes J Invest Dermatol 18496568

Cited by

Sorted by citations

Authors
Kyriakides, T. R., Wulsin, D., Skokos, E. A., Fleckman, P., Pirrone, A., Shipley, J. M., Senior, R. M., & Bornstein, P.
Affiliations
  • Yale University (US)
  • University of Washington (US)
  • Washington University in St. Louis (US)
Corresponding author
Kyriakides, Themis R.
ORCID
Kyriakides, Themis R.
Venue
Matrix Biology
Publisher
Elsevier BV
Published
2009-03
Volume
28
Issue
2
Pages
65-73
ISSN
0945-053X (ISSN-L)
DOI
10.1016/j.matbio.2009.01.001
PMC
PMC2673333
OpenAlex
W2126919832
Cited by
173
References
3
Citations by year
2026: 6 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 10 · 2016: 9 · 2015: 18 · 2014: 12 · 2013: 16 · 2012: 15
FWCI
13.58
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Matrix Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01gm072194-11)
  • National Heart, Lung, and Blood Institute (R01HL047328, HL 47328)
  • National Institute of General Medical Sciences (R01-GM072194, GM-072194-01)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR045418, AR-45418)
Topics
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
MMP-9, wound healing, re-epithelialization, collagen fibrillogenesis, extracellular matrix deposition, keratinocyte migration, angiogenesis, vascular endothelial growth factor, full-thickness skin wounds, wound tensile strength
MeSH terms
Animals, Cell Movement, Collagen, Epithelium, Extracellular Matrix, Fibrin, Humans, Immunohistochemistry, Skin, Tensile Strength, Wound Healing, Keratinocytes, Matrix Metalloproteinase 9, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review