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Wound Fluids from Human Pressure Ulcers Contain Elevated Matrix Metalloproteinase Levels and Activity Compared to Surgical Wound Fluids
Open accessAbstract
Fluid from acute surgical wounds and from nonhealing pressure ulcers was examined for the presence of several matrix metalloproteinases. Gelatin zymography demonstrated the presence of two major gelatinases with apparent molecular masses of 72 kDa and 92 kDa and two minor gelatinases with apparent mobilities of 68 kDa and 125 kDa. Antigen-specific sera identified the 72-kDa protein as matrix melloproteinase-2. The same sera also reacted with the 68-kDa protein, which is consistent with it being an activated form of matrix metalloproteinase-2. Antigen-specific sera identified the 92-kDa and 125-kDa proteins as matrix metalloproteinase-9. Levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were elevated more than 10-fold and 25-fold, respectively, in fluids from pressure ulcers compared with fluids from healing wounds. Examination of total potential and actual collagenolytic activity revealed that fluid from pressure ulcers contained significantly greater levels of both total and active collagenase compared with that of acute surgical wounds. In addition, an enzyme-linked immunosorbent assay demonstrated that fluids from pressure ulcers contained significantly more collagenase complexed with the inhibitor, tissue inhibitor of metalloproteinases. Together, these observations suggest that an imbalance exists between levels of matrix metalloproteinases and their inhibitors in the fluids of pressure ulcers and that this is primarily the result of elevated levels of the matrix metalloproteinases. The presence of excessive levels of activated forms of matrix-degrading enzymes at the wound surface of pressure ulcers may impede the healing of these wounds and may be relevant to the development of new rationales for treatment.
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“Last, in chronic wounds, there is a marked increase in serine proteases that degrades matrix components, including fibronectin, as well as various key growth factors, all of which are required for remodeling of the ECM and cell growth (38-41).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [38]
In the citing paper
“It has been shown that matrix metalloproteinases (MMPs), such as collagenase and gelatinases A and B, are elevated in chronic wound fluids when compared to acute wound fluid (25, 38).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [38]
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“The inability to correctly regulate MMP activity in wound healing could prevent or delay healing.(15)”
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“…a-ACT, a-1-antichymotrypsin; a-AT, a-1-antitrypsin; IKC, immortalized human keratinocyte; MMP, matrix metalloproteinase; RCL, reactive center loop; TGF-b, transforming growth factor-b; TNF-a, tumor necrosis factor-a 1996; Yager et al., 1996; Han et al., 2001b; Ladwig et al., 2002).”
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Wound Fluid in Diabetic Foot Ulceration
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“MMP-2 levels have been shown by a number of studies to be significantly increased over controls or to have a relationship to wound healing in wound fluid [43, 46, 57, 63, 80, 82] as well as wound tissue [79, 89, 90].”
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“10-fold increases in MMP levels were found in chronic leg ulcers compared to acute healing wounds; these elevated levels of MMPs explain the turnover in chronic tissue and failed wound closure [16-19].”
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“Comparison of levels of cytokines, chemokines, andMMPs demonstrated no relevant loss of analytes when using the swabbing technique compared with the currently available standard method.”
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“MMP concentrations in our study were shown to be comparable to those in other previous studies that examined the levels in would fluid and expressed the values in the same unit (pg/μg of protein) [18].”
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“This work may also have implications beyond DFUs as MMPs are up-regulated in PUs and VLUs ( 66 , 67 ), which are also commonly colonized by A. faecalis (Table 1).”
An MMP/TIMP ratio scoring system as a potential predictive marker of diabetic foot ulcer healing
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“Previous studies have shown that various proteases could serve as biomarkers of poor healing (22, 30, 31).”
BackgroundIFN-α2b Suppresses the Fibrogenic Effects of Insulin-Like Growth Factor-1 in Dermal Fibroblasts
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Acute and chronic wound fluids influence keratinocyte function differently
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“In most studies, the average level of growth factors in CWF was shown to be significantly lower than that in AWF (16,17).”
BackgroundResultNovel protease‐based diagnostic devices for detection of wound infection
Heinzle, A., Papen‐Botterhuis, N. E., Schiffer, D., Schneider, K. P., Binder, B., SCHINTLER, M. V., Haaksman, I. K., Lenting, H. B. M., Guebitz, G. M., & Sigl, E. (2013) · Wound Repair and Regeneration · doi:10.1111/wrr.12040 · Cited by 32
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Self-citationPropranolol impairs the closure of pressure ulcers in mice
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“Ulcer microenvironment shows a massive destruction of extracellular matrix (ECM) and growth factors due to the invasion of tremendous number of neutrophils and their destructive enzymes, as neutrophil elastase and MMP-8 (Diegelmann, 2003; Nwomeh et al., 1999; Yager et al., 1996).”
BackgroundMMP-2 Assessment as an Indicator of Wound Healing
Karim, R. B., Brito, B. L. R., Dutrieux, R. P., Lassance, F. P., & Hage, J. J. (2006) · Advances in Skin & Wound Care · doi:10.1097/00129334-200607000-00011 · Cited by 31
“Activated MMP-2 protein, however, is higher in chronic wounds.(20-22) Because of the difference between MMP2 expression levels in inert and healing wounds, specific tissue staining may effectively determine wound state and changes induced by therapeutic interventions.”
BackgroundCastronuovo, J., Ghobrial, I. I., Giusti, A., Rudolph, S., & Smiell, J. M. (1998) · The American Journal of Surgery · doi:10.1016/s0002-9610(98)00175-5 · Cited by 30
Edwards, J. V., Bopp, A. F., Batiste, S. L., Ullah, A. J., Cohen, I. K., Diegelmann, R. F., & Montante, S. J. (1999) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1999.00106.x · Cited by 30
Self-citationZhao, X., Liu, R., Tang, T., Liu, Z., Liu, X., Yu, K., Zhang, Y., & Wang, H. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.152875 · Cited by 29
Loo, W. T. Y., Sasano, H., & Chow, L. W. C. (2007) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2007.08.012 · Cited by 29
MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF‐β1 levels
Jiang, D., Singh, K., Muschhammer, J., Schatz, S., Sindrilaru, A., Makrantonaki, E., Yu, Q., Wlaschek, M., & Scharffetter‐Kochanek, K. (2020) · EMBO Reports · doi:10.15252/embr.201949115 · Cited by 28
“In fact, recombinant TGF-b 1 is easily degraded in chronic human wounds [55,56], and repetitive injections of recombinant TGF-b 1 into fibrotic wound edges so far have neither been successful nor established in clinical routine.”
Woo, K. Y., Dowsett, C., Costa, B., Ebohon, S., Woodmansey, E. J., & Malone, M. (2021) · International Wound Journal · doi:10.1111/iwj.13560 · Cited by 28
Protease inhibition by oleic acid transfer from chronic wound dressings to albumin
Edwards, J. G., HOWLEY, P., Davis, R. G., Mashchak, A., & Goheen, S. C. (2007) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.03.018 · Cited by 28
“Oleic acid is a non-toxic elastase inhibitor.”
BackgroundInfluentialKroeze, K. L., Vink, L., Boer, E. M. D., Scheper, R. J., van Montfrans, C., & Gibbs, S. (2012) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2012.00789.x · Cited by 28
Tejiram, S., Kavalukas, S. L., Shupp, J. W., & Barbul, A. (2016) · Elsevier eBooks · doi:10.1016/b978-1-78242-455-0.00001-x · Cited by 28
Kumar, M., Sethi, P., Shiekmydeen, J., Rastogi, S., Mahmood, S., Chopra, S., Thomas, S., Kumar, D., & Bhatia, A. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.144251 · Cited by 32
Complications of Wound Healing
Basu, S., & Shukla, V. K. (2012) · Springer eBooks · doi:10.1007/978-1-4471-2987-5_7 · Cited by 26
Epigenetics: key to improve delayed wound healing in type 2 diabetes
Dubey, R., Prabhakar, P. K., & Gupta, J. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04285-0 · Cited by 30
Advances in the Sensing and Treatment of Wound Biofilms
Darvishi, S., Tavakoli, S., Kharaziha, M., Girault, H. H., Kaminski, C. F., & Mela, I. (2021) · Angewandte Chemie · doi:10.1002/ange.202112218 · Cited by 30
Su, C., Liu, S., Yu, S.-Y., Hsieh, Y.-L., Ho, H., Hu, C., & Sheu, M. (2004) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.30235 · Cited by 27
Poursamar, S. A., Hatami, J., Lehner, A. N., da Silva, C. L., Ferreira, F. C., & Antunes, A. P. M. (2016) · International Journal of Polymeric Materials · doi:10.1080/00914037.2015.1119688 · Cited by 27
Cakin, M. C., Özdemir, B., Dağıstanlı, F. K., Arkan, H., Bahtiyar, N., Anapalı, M., Akbaş, F., & Onaran, İ. (2019) · Platelets · doi:10.1080/09537104.2019.1663805 · Cited by 27
“healing increases proteolytic activity within wounds, exerting an effect against peptide growth factors [7,8].”
BackgroundYamanaka, M., & Ishikawa, O. (2000) · Journal of Dermatological Science · doi:10.1016/s0923-1811(00)00086-4 · Cited by 27
“It was reported that wound fluids from chronic skin ulcers contained elevated levels of MMPs: MMP-1, MMP-8, MMP-2 and MMP-9 [16–19].”
BackgroundImmunregulation der Wundheilung
Schäffer, M. R., & Becker, H. D. (1999) · Der Chirurg · doi:10.1007/s001040050740 · Cited by 27
“Entsprechend konnte in chronischen Wunden eine im Vergleich zu akuten Wunden erhöhte Expression von MMP-2 und MMP-9 sowie eine verminderte Aktivität von TIMP-1 dokumentiert werden [69].”
BackgroundNegative pressure wound therapy achieved by vacuum-assisted closure: Evaluating the assumptions.
Morris, G. S., Brueilly, K. E., & Hanzelka, H. (2007) · PubMed · Cited by 26
Jana, S., Datta, P., Das, H., Jaiswal, S., Ghosh, P. R., Debrupa Lahiri, A., Kundu, B., & Nandi, S. K. (2022) · Journal of the mechanical behavior of biomedical materials/Journal of mechanical behavior of biomedical materials · doi:10.1016/j.jmbbm.2022.105414 · Cited by 26
Interleukin-1α–induced proteolytic activation of metalloproteinase-9 by human skin
Han, Y., Downey, S. E., & Garner, W. L. (2005) · Surgery · doi:10.1016/j.surg.2005.05.003 · Cited by 26
Physiology and Pathophysiology of Wound Healing in Diabetes
Pastar, I., Balukoff, N. C., Sawaya, A. P., Vecin, N. M., & Tomic‐Canic, M. (2024) · Contemporary diabetes · doi:10.1007/978-3-031-55715-6_7 · Cited by 27
Gowda, S., Weinstein, D. A., Blalock, T. D., Gandhi, K., Mast, B. A., Chin, G. A., & Schultz, G. S. (2013) · International Wound Journal · doi:10.1111/iwj.12165 · Cited by 25
Correlation between interleukin‐6 and matrix metalloproteinase‐9 in early wound healing in children
Pajulo, O. T., Pulkki, K. J., Alanen, M. S., Reunanen, M. S., Lertola, K., Mattila‐Vuori, A. I., & Viljanto, J. A. (1999) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1999.00453.x · Cited by 25
Approaches to Control and Monitor Protease Levels in Chronic Wounds
Kolahreez, D., Ghasemi‐Mobarakeh, L., Liebner, F. W., Alihosseini, F., Quartinello, F., Guebitz, G. M., & Ribitsch, D. (2024) · Advanced Therapeutics · doi:10.1002/adtp.202300396 · Cited by 24
Tsilingiris, D., Natsi, A., Gavriilidis, E., Antoniadou, C., Eleftheriadou, I., Anastasiou, I. A., Tentolouris, A., Papadimitriou, E., Eftalitsidis, E., Kolovos, P., et al. (2025) · European Journal of Immunology · doi:10.1002/eji.202451664 · Cited by 24
“Excessive MMP-9 activity has also been implicated in poor healing in cutaneous wounds in conditions other than T2D, such as chronic pressure [30] and venous [31] ulcers.”
Proteolytic signatures define unique thrombin-derived peptides present in human wound fluid in vivo
Saravanan, R., Adav, S. S., Choong, Y. K., van der Plas, M. J. A., Petrlová, J., Kjellström, S., Sze, S. K., & Schmidtchen, A. (2017) · Scientific Reports · doi:10.1038/s41598-017-13197-3 · Cited by 24
“Other researchers are focusing on protein patterns, and identification of the total proteome of wounds has been suggested as one method to obtain not only information of the pathogenesis, but also to be able to define specific protein biomarkers discriminating between various wound types 29–31 .”
Method
Metadata
- Authors
- Yager, D. R., Zhang, L.-Y., Liang, H.-X., Diegelmann, R. F., & Cohen, I. K.
- Affiliations
- Virginia Commonwealth University Medical Center (US)
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 1996-11
- Volume
- 107
- Issue
- 5
- Pages
- 743-748
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2061992885
- Cited by
- 389
- References
- 41
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 9 · 2021: 20 · 2020: 9 · 2019: 9 · 2018: 16 · 2017: 11 · 2016: 23 · 2015: 16 · 2014: 17 · 2013: 18 · 2012: 21
- FWCI
- 4.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01gm047566-08)
- National Institute of General Medical Sciences (GM-47566, GM20298)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Health Sciences › Medicine › Dermatology › Pressure Ulcer Prevention and Management
- Keywords
- pressure ulcers, matrix metalloproteinases, MMP-2, MMP-9, wound fluid, surgical wounds, collagenase, tissue inhibitors of metalloproteinases, chronic wounds, wound healing, gelatinase
- MeSH terms
- Animals, Pressure Ulcer, Glycoproteins, Humans, Metalloendopeptidases, Rabbits, Surgical Procedures, Operative, Wound Healing, Collagenases, Gelatinases, Tissue Inhibitor of Metalloproteinases, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9
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