Targeting MMP-9 in Diabetic Foot Ulcers

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2019 May 25

PMID 31121851

Citations 27

Authors

Jeffrey I Jones

Trung T Nguyen

Zhihong Peng

Mayland Chang

Affiliations

Soon will be listed here.

Abstract

Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology of wounds and in the wound healing process. However, because of the challenge in distinguishing active MMPs from the two catalytically inactive forms of MMPs and the clinical failure of broad-spectrum MMP inhibitors in cancer, MMPs have not been a target for treatment of DFUs until recently. This review covers the discovery of active MMP-9 as the biochemical culprit in the recalcitrance of diabetic wounds to healing and targeting this proteinase as a novel approach for the treatment of DFUs. Active MMP-8 and MMP-9 were observed in mouse and human diabetic wounds using a batimastat affinity resin and proteomics. MMP-9 was shown to play a detrimental role in diabetic wound healing, whereas MMP-8 was beneficial. A new class of selective MMP-9 inhibitors shows clinical promise for the treatment of DFUs.

Citing Articles

Amine-Functionalized Gellan Gum-Based Hydrogel Loaded with Adipose Stem Cell-Derived Small Extracellular Vesicles: An In Vitro Proof of Concept for Enhancing Diabetic Foot Ulcer Healing.

Tomasello L, Biondo M, Biscari G, Di Rosa L, Palumbo F, Fiorica C Gels. 2025; 11(2).

PMID: 39996662 PMC: 11854167. DOI: 10.3390/gels11020119.

Computational Elucidation of Human β-Defensin-2 as a Dual Inhibitor of MMP-9 and PKC-βII for Diabetic Wound Management.

Sanapalli V, Sigalapalli D, Shaik A, Bhandare R, Sanapalli B ACS Omega. 2025; 10(4):3575-3584.

PMID: 39926537 PMC: 11800154. DOI: 10.1021/acsomega.4c08292.

Repurposing diacerein for the treatment of chronic wounds in recessive-dystrophic epidermolysis bullosa patients by modulating matrix metalloproteinase-9 expression.

Dorfer S, Ablinger M, Wimmer M, Hummel J, Ibrahimpasic S, Diem A J Dermatol. 2025; 52(3):423-431.

PMID: 39853777 PMC: 11883725. DOI: 10.1111/1346-8138.17621.

Therapeutic potential of microRNA-engineered exosomes in diabetic wound healing: a meta-analysis.

Jian X, Han J, Chen J, Xiao S, Deng C Arch Dermatol Res. 2024; 316(8):493.

PMID: 39066806 DOI: 10.1007/s00403-024-03234-3.

Matrix Metalloproteinase-9 Testing of Golden Rice Cookies With Piper Crocatum Active Extract for Preventing Foot Ulcers in Patients With Diabetes: Protocol for a Randomized Controlled Trial.

Setyawati A, Saleh A, Tahir T, Yusuf S, Syahrul S, Aminuddin A JMIR Res Protoc. 2024; 13:e49940.

PMID: 38422498 PMC: 10940992. DOI: 10.2196/49940.

References

Trengove N, Stacey M, Macauley S, Bennett N, Gibson J, Burslem F . Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair Regen. 2000; 7(6):442-52. DOI: 10.1046/j.1524-475x.1999.00442.x. View

Greene A, Puder M, Roy R, Arsenault D, Kwei S, Moses M . Microdeformational wound therapy: effects on angiogenesis and matrix metalloproteinases in chronic wounds of 3 debilitated patients. Ann Plast Surg. 2006; 56(4):418-22. DOI: 10.1097/01.sap.0000202831.43294.02. View

Moues C, van Toorenenbergen A, Heule F, Hop W, Hovius S . The role of topical negative pressure in wound repair: expression of biochemical markers in wound fluid during wound healing. Wound Repair Regen. 2008; 16(4):488-94. DOI: 10.1111/j.1524-475X.2008.00395.x. View

Forbes C, Shi Q, Fisher J, Lee M, Hesek D, Llarrull L . Active site ring-opening of a thiirane moiety and picomolar inhibition of gelatinases. Chem Biol Drug Des. 2009; 74(6):527-34. PMC: 2837476. DOI: 10.1111/j.1747-0285.2009.00881.x. View

Vandenbroucke R, Libert C . Is there new hope for therapeutic matrix metalloproteinase inhibition?. Nat Rev Drug Discov. 2014; 13(12):904-27. DOI: 10.1038/nrd4390. View

Xu F, Zhang Z, Ping Y, Li J, Kang E, Neoh K . Star-shaped cationic polymers by atom transfer radical polymerization from beta-cyclodextrin cores for nonviral gene delivery. Biomacromolecules. 2009; 10(2):285-93. DOI: 10.1021/bm8010165. View

McCawley L, Matrisian L . Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today. 2000; 6(4):149-56. DOI: 10.1016/s1357-4310(00)01686-5. View

DeClerck Y, Imren S . Protease inhibitors: role and potential therapeutic use in human cancer. Eur J Cancer. 1994; 30A(14):2170-80. DOI: 10.1016/0959-8049(94)00460-m. View

Overall C, Kleifeld O . Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer. 2006; 94(7):941-6. PMC: 2361222. DOI: 10.1038/sj.bjc.6603043. View

10.

Gao M, Nguyen T, Suckow M, Wolter W, Gooyit M, Mobashery S . Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy. Proc Natl Acad Sci U S A. 2015; 112(49):15226-31. PMC: 4679041. DOI: 10.1073/pnas.1517847112. View

11.

Hesek D, Toth M, Krchnak V, Fridman R, Mobashery S . Synthesis of an inhibitor-tethered resin for detection of active matrix metalloproteinases involved in disease. J Org Chem. 2006; 71(16):5848-54. DOI: 10.1021/jo060058h. View

12.

Vuerstaek J, Vainas T, Wuite J, Nelemans P, Neumann M, Veraart J . State-of-the-art treatment of chronic leg ulcers: A randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg. 2006; 44(5):1029-37. DOI: 10.1016/j.jvs.2006.07.030. View

13.

Tsang K, Kwong E, To T, Chung J, Wong T . A Pilot Randomized, Controlled Study of Nanocrystalline Silver, Manuka Honey, and Conventional Dressing in Healing Diabetic Foot Ulcer. Evid Based Complement Alternat Med. 2017; 2017:5294890. PMC: 5296609. DOI: 10.1155/2017/5294890. View

14.

Baker A, Edwards D, Murphy G . Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci. 2002; 115(Pt 19):3719-27. DOI: 10.1242/jcs.00063. View

15.

Nguyen T, Ding D, Wolter W, Perez R, Champion M, Mahasenan K . 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(19):8825-8837. DOI: 10.1021/acs.jmedchem.8b01005. View

16.

Lazaro J, Izzo V, Meaume S, Davies A, Lobmann R, Uccioli L . Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. J Wound Care. 2016; 25(5):277-87. DOI: 10.12968/jowc.2016.25.5.277. View

17.

Kucharzewski M, Rojczyk E, Wilemska-Kucharzewska K, Wilk R, Hudecki J, Los M . Novel trends in application of stem cells in skin wound healing. Eur J Pharmacol. 2018; 843:307-315. DOI: 10.1016/j.ejphar.2018.12.012. View

18.

Jeong E, Kim H, Jang B, Cho H, Ryu J, Kim B . Technological development of structural DNA/RNA-based RNAi systems and their applications. Adv Drug Deliv Rev. 2015; 104:29-43. DOI: 10.1016/j.addr.2015.10.008. View

19.

Vukelic S, Griendling K . Angiotensin II, from vasoconstrictor to growth factor: a paradigm shift. Circ Res. 2014; 114(5):754-7. PMC: 3985550. DOI: 10.1161/CIRCRESAHA.114.303045. View

20.

Nguyen T, Ding D, Wolter W, Champion M, Hesek D, Lee M . Expression of active matrix metalloproteinase-9 as a likely contributor to the clinical failure of aclerastide in treatment of diabetic foot ulcers. Eur J Pharmacol. 2018; 834:77-83. PMC: 6205151. DOI: 10.1016/j.ejphar.2018.07.014. View