Download PDF
Horm Metab Res 2023; 55(11): 752-757
DOI: 10.1055/a-2171-5879
Review

Based on Clinical Research Matrix Metalloprotease (MMP) Inhibitors to Promote Diabetic Wound Healing

Jagat Pal Yadav
1   Faculty of Pharmaceutical Sciences, Rama University, Kanpur, India
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Chronic inflammation is a common factor in obesity, diabetes mellitus, and the complications of diabetes, including diabetic wounds. These ulcers are characterized by persistent lesions that are challenging to heal, significantly decreasing patients’ quality of life and imposing a substantial financial burden on society. MMP are zinc endopeptidases that play a role in wound healing in response to various stimuli, including diabetes mellitus. MMP levels fluctuate throughout the wound healing process in diabetic patients' serum, skin tissues, and wound fluid, indicating their potential as biomarkers for diabetic foot ulcers. Targeting MMP has emerged as a promising strategy for treating diabetic wounds, as these enzymes are involved in critical biological processes related to wound healing, including extracellular matrix secretion, angiogenesis, granulation tissue formation, collagen growth, re-epithelization, inflammatory response, and oxidative stress.

Key words

MMPs - diabetic wound - NF-kB - FOXO-1 - stem cells


Publication History

Received: 29 March 2023

Accepted after revision: 01 September 2023

Article published online:
05 October 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Whiting DR, Guariguata L, Weil C. et al. IDF Diabetes Atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011; 94: 311-321
    CrossrefPubMedGoogle Scholar
  • 2 Yadav JP, Grishina M, Shahbaaz M. et al. Cucumis melo var. momordica as a potent antidiabetic, antioxidant and possible anticovid alternative: investigation through experimental and computational methods. Chem Biodivers 2022; 19: e202200200
    CrossrefPubMedGoogle Scholar
  • 3 Vijayakumar V, Samal SK, Mohanty S. et al. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int J Biol Macromol 2019; 122: 137-148
    CrossrefPubMedGoogle Scholar
  • 4 Sinwar PD. The diabetic foot management - recent advance. Int J Surg 2015; 15: 27-30
    CrossrefPubMedGoogle Scholar
  • 5 Yadav JP, Patel DK, Pathak P. et al. Role of G-protein coupled receptor (GPCRs)/(GPR-120) as an agonists in diabetic wound healing. Obes Med 2022; 36: 100466
    CrossrefPubMedGoogle Scholar
  • 6 Cho H, Blatchley MR, Duh EJ. et al. Acellular and cellular approaches to improve diabetic wound healing. Adv Drug Deliv Rev 2019; 146: 267-288
    CrossrefPubMedGoogle Scholar
  • 7 Yadav JP, Patel DK, Dubey NK. et al. Wound healing and antioxidant potential of Neolamarckia cadamba in streptozotocin-nicotinamide induced diabetic rats. Phytomedicine Plus 2022; 2: 100274
    CrossrefPubMedGoogle Scholar
  • 8 Lobmann R, Zemlin C, Motzkau M. et al. Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing. J Diabetes Complicat 2006; 20: 329-335
    CrossrefPubMedGoogle Scholar
  • 9 Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes and approaches to care. Adv Ski Wound Care 2012; 25: 349-370
    CrossrefPubMedGoogle Scholar
  • 10 auf dem Keller U, Sabino F. Matrix metalloproteinases in impaired wound healing. Met Med 2015; 9: 1-8
    PubMedGoogle Scholar
  • 11 Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C. et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 2020; 21: 1-53
    CrossrefPubMedGoogle Scholar
  • 12 Lobmann R, Ambrosch A, Schultz G. et al. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 2002; 45: 1011-1016
    CrossrefPubMedGoogle Scholar
  • 13 Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol 2015; 44–46: 247-254
    CrossrefPubMedGoogle Scholar
  • 14 Chang M, Nguyen TT. Strategy for treatment of infected diabetic foot ulcers. Acc Chem Res 2021; 54: 1080-1093
    CrossrefPubMedGoogle Scholar
  • 15 Zhou L, Ren M, Zeng T. et al. TET2-interacting long noncoding RNA promotes active DNA demethylation of the MMP-9 promoter in diabetic wound healing. Cell Death Dis 2019; 10: 813
    CrossrefPubMedGoogle Scholar
  • 16 Hu H, Jiang H, Ren H. et al. AGEs and chronic subclinical inflammation in diabetes: disorders of immune system. Diabetes Metab Res Rev 2015; 31: 127-137
    CrossrefPubMedGoogle Scholar
  • 17 De Mayo T, Conget P, Becerra-Bayona S. et al. The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice. PLoS One 2017; 12: 1-17
    CrossrefPubMedGoogle Scholar
  • 18 Zhu P, Chen C, Wu D. et al. AGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats. Diabetes Res Clin Pract 2022; 186: 1-5
    PubMedGoogle Scholar
  • 19 Zhu P, Ren M, Yang C. et al. Involvement of RAGE, MAPK and NF-κB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes. Exp Dermatol 2012; 21: 123-129
    CrossrefPubMedGoogle Scholar
  • 20 Huang SM, Wu CS, Chiu MH. et al. High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-α: An important mechanism to delay the diabetic wound healing. J Dermatol Sci 2019; 96: 159-167
    CrossrefPubMedGoogle Scholar
  • 21 Wang Y, Graves DT. Keratinocyte function in normal and diabetic wounds and modulation by FoxO1. J Diabetes Res 2020; 3714704
    PubMedGoogle Scholar
  • 22 Hameedaldeen A, Liu J, Batres A. et al. FOXO1, TGF-β regulation and wound healing. Int J Mol Sci 2014; 15: 16257-16269
    CrossrefPubMedGoogle Scholar
  • 23 Patel S, Srivastava S, Singh MR. et al. Biomedicine & pharmacotherapy mechanistic insight into diabetic wounds: pathogenesis , molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother 2019; 112: 108615
    CrossrefPubMedGoogle Scholar
  • 24 Zhang C, Lim J, Jeon HH. et al. FOXO1 deletion in keratinocytes improves diabetic wound healing through MMP9 regulation. Sci Rep 2017; 7: 1-9
    CrossrefPubMedGoogle Scholar
  • 25 Xu J, Zgheib C, Hodges MM. et al. Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis. Physiol Genomics 2017; 49: 541-548
    CrossrefPubMedGoogle Scholar
  • 26 Gadelkarim M, Abushouk AI, Ghanem E. et al. Adipose-derived stem cells: Effectiveness and advances in delivery in diabetic wound healing. Biomed Pharmacother 2018; 107: 625-633
    CrossrefPubMedGoogle Scholar
  • 27 Zhang N, Yu X, Li W. et al. Extracellular vesicles derived from adipose-derived stem cells facilitate frostbite wound healing by regulating SOCS3 expression. Curr Stem Cell Res Ther 2022; 18: 528-539
    CrossrefPubMedGoogle Scholar
  • 28 Kato J, Kamiya H, Himeno T. et al. Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats. J Diabetes Complicat 2014; 28: 588-595
    CrossrefPubMedGoogle Scholar
  • 29 Lv Y, Ge LH, Zhao YM. Effect and mechanism of SHED on ulcer wound healing in Sprague-Dawley rat models with diabetic ulcer. Am J Transl Res 2017; 9: 489-498
    PubMedGoogle Scholar
  • 30 Balaji S, Han N, Moles C. et al. Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds. Surg (United States) 2015; 158: 846-856
    PubMedGoogle Scholar
  • 31 Deng L, Du C, Song P. et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid Med Cell Longev 2021; 2021: 1-11
    CrossrefPubMedGoogle Scholar
  • 32 Gao M, Nguyen TT, Suckow MA. et al. Acceleration of diabetic wound healing using a novel proteaseanti-protease combination therapy. Proc Natl Acad Sci U S A 2015; 112: 15226-15231
    CrossrefPubMedGoogle Scholar
  • 33 Wu X, He W, Mu X. et al. Macrophage polarization in diabetic wound healing. Burns & Trauma 2022; 10: tkac051
    CrossrefPubMedGoogle Scholar
  • 34 Yadav JP, Singh AK, Grishina M. et al. Cucumis melo Var. agrestis Naudin as a potent antidiabetic: Investigation via experimental methods. Phytomed Plus 2022; 2: 100340
    CrossrefPubMedGoogle Scholar
  • 35 Ling L, Ren M, Yang C. et al. Role of site-specific DNA demethylation in TNFα -induced MMP9 expression in keratinocytes. Soc Endocrinol 2013; 50: 279-290
    PubMedGoogle Scholar
  • 36 Lu W, Li J, Ren M. et al. Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes. Mol Cell Endocrinol 2015; 411: 121-129
    CrossrefPubMedGoogle Scholar
  • 37 Zhang J, Yang C, Wang C. et al. AGE-induced keratinocyte MMP-9 expression is linked to TET2-mediated CpG demethylation. Wound Rep Reg 2016; 24: 489-500
    CrossrefPubMedGoogle Scholar
  • 38 Jindatanmanusan P, Luanraksa S, Boonsiri T. et al. Wound fluid matrix metalloproteinase-9 as a potential predictive marker for the poor healing outcome in diabetic foot ulcers. Patholog Res Int 2018; 2018: 1-5
    CrossrefPubMedGoogle Scholar
  • 39 Liu Y, Min D, Bolton T. et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care 2009; 32: 117-119
    CrossrefPubMedGoogle Scholar
  • 40 Singh K, Agrawal NK, Gupta SK. et al. A functional single nucleotide polymorphism -1562c>t in the matrix metalloproteinase-9 promoter is associated with type 2 diabetes and diabetic foot ulcers. Int J Low Extrem Wounds 2013; 12: 199-204
    CrossrefPubMedGoogle Scholar
  • 41 Trøstrup H, Holstein P, Karlsmark T. et al. Uncontrolled gelatin degradation in non-healing chronic wounds. J Wound Care 2018; 27: 724-734
    CrossrefPubMedGoogle Scholar
  • 42 Dinh T, Tecilazich F, Kafanas A. et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes 2012; 61: 2937-2947
    CrossrefPubMedGoogle Scholar
  • 43 Li G, Zou X, Zhu Y. et al. Expression and influence of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor in diabetic foot ulcers. Int J Low Extrem Wounds 2017; 16: 6-13
    CrossrefPubMedGoogle Scholar
  • 44 Menghini R, Uccioli L, Vainieri E. et al. Expression of tissue inhibitor of metalloprotease 3 is reduced in ischemic but not neuropathic ulcers from patients with type 2 diabetes mellitus. Acta diabetologica 2013; 50: 907-910
    CrossrefPubMedGoogle Scholar
  • 45 Min D, Nube V, Tao A. et al. Monocyte phenotype as a predictive marker for wound healing in diabetes-related foot ulcers. J Diabetes Complicat 2021; 35: 107889
    CrossrefPubMedGoogle Scholar
  • 46 Kupczyk D, Bilski R, Studzińska R. et al. Assessment of the concentration of selected metalloproteinases (MMP-2, MMP-3, MMP-9 and MMP-13) in patients with ulcers as a complication of type 2 diabetes. Adv Dermatol Allergol 2020; 39: 59-65
    CrossrefPubMedGoogle Scholar
  • 47 Nguyen TT, Ding D, Wolter WR. et al. Validation of matrix metalloproteinase-9 ( MMP-9 ) as a novel target for treatment of diabetic foot ulcers in humans and discovery of a potent and selective small-molecule MMP-9 inhibitor that accelerates healing. J Med Chem 2018; 61: 8825-8837
    CrossrefPubMedGoogle Scholar
  • 48 Hilton JR, Williams DT, Beuker B. et al. Wound dressings in diabetic foot disease 2004; 39: 14-17
    PubMed
  • 49 Hiller J, Stratmann B, Timm J. et al. Enhanced growth factor expression in chronic diabetic wounds treated by cold atmospheric plasma. Diabet Med 2022; 39: e14787
    CrossrefPubMedGoogle Scholar
  • 50 Rayment EA, Dargaville TR, Shooter GK. et al. Attenuation of protease activity in chronic wound fluid with bisphosphonate-functionalised hydrogels. Biomaterials 2008; 29: 1785-1795
    CrossrefPubMedGoogle Scholar