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Matrix metalloproteinases: the role in evolution of liver diseases

Pavel Koroy; Temirlan Ruslanovich Dudov; Alexandr Yagoda; Vijaya Sarithala;

Chronic liver diseases are characterized by the activation of stellate cells and increased extracellular matrix (ECM) accumulation, which leads to the evolution and advancement of liver fibrosis. Hepatic fibrogenesis is based on an imbalance between the collection and degradation of ECM, caused, among other things, by impaired matrix metalloproteinases (MMPs) expression. The review presents data on the biological role of various MMPs in normal and liver diseases. Clarifying the place of MMP in noninvasive and early diagnosis of chronic liver diseases will optimize the management of this category of patients.


1. Duarte S., Baber J., Fujii T., Coito A. J. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol. 2015;44-46:147-156. https://doi.org/10.1016/j.matbio.2015.01.004
2. Geervliet E., Bansal R. Matrix metalloproteinases as potential biomarkers and therapeutic targets in liver diseases. Cells. 2020;9(5):1212. https://doi.org/10.3390/cells9051212
3. Jabłońska-Trypuć A., Matejczyk M., Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J. Enzyme Inhib. Med. Chem. 2016;3(1):177-183. https://doi.org/10.3109/14756366.2016.1161620
4. Arteel G. E., Naba A. The liver matrisome – looking beyond collagens. JHEP Reports. 2020;2(4):100115. https://doi.org/10.1016/j.jhepr.2020.100115
5. Chen G., Xia B., Fu Q., Huang X., Wang F. [et al.] Matrix mechanics as regulatory factors and therapeutic targets in hepatic fibrosis. Int. J. Biol. Sci. 2019;15(12):2509-2521. https://doi.org/10.7150/ijbs.37500
6. Naim A., Pan Q., Baig M. S. Matrix metalloproteinases (MMPs) in liver diseases. J. Clin. Exp. Hepatol. 2017;7(4):367-372. https://doi.org/10.1016/j.jceh.2017.09.004
7. Robert S., Gicquel T., Bodin A., Lagente V., Boichot E. Characterization of the MMP/TIMP imbalance and collagen production induced by IL-1β or TNF-α release from human hepatic stellate cells. PLoS One. 2016;11(4):e0153118. https://doi.org/10.1371/journal.pone.0153118
8. Roeb E. Matrix metalloproteinases and liver fibrosis (translational aspects). Matrix Biol. 2018;68-69:463-473. https://doi.org/10.1016/j.matbio.2017.12.012
9. Shadrina A. S., Plieva Ya. Z., Kushlinskii D. N., Morozov A. A., Filipenko M. L. [et al.] Classification, regulation of activity, genetic polymorphism of matrix metalloproteinases in normal and pathological conditions. Al’manah klinicheskoj mediciny. – Almanac of Clinical Medicine. 2017;45(4):266-279. https://doi.org/10.18786/2072-0505-2017-45-4-266-279
10. Binder M. J., McCoombe S., Williams E. D., McCulloch D., Ward A. The extracellular matrix in cancer progression: Role of hyalectan proteoglycans and ADAMTS enzymes. Cancer Lett. 2017;385:55-64. https://doi.org/10.1016/j.canlet.2016.11.001
11. Apte S. S., Parks W. C. Metalloproteinases: a parade of functions in matrix biology and an outlook for the future. Matrix Biology. 2015;44-46:1-6. https://doi.org/10.1016/j.matbio.2015.04.005
12. Chen J., Xu W., Chen Y., Xie X., Zhang Y. [et al.] Matrix metalloproteinase 9 facilitates hepatitis B virus replication through binding with type I interferon (IFN) receptor 1 to repress IFN/JAK/STAT signaling. Virol. 2017.91(8):e01824-16. https://doi.org/10.1128/JVI.01824-16
13. Ulitzky L., Lafer M. M., KuKuruga M. A., Silberstein E., Cehan N., Taylor D. R. A new signaling pathway for HCV inhibition by estrogen: GPR30 activation leads to cleavage of occludin by MMP-9. PLoS One. 2016;11(1):e0145212. https://doi.org/10.1371/journal.pone.0145212
14. Chuang H.-M., Chen Y.-S., Harn H.-J. The Versatile role of matrix metalloproteinase for the diverse results of fibrosis treatment. Molecules. 2019;24(22):4188. https://doi.org/10.3390/molecules24224188
15. Grigorkevich O. S., Mokrov G. V., Kosova L. Yu. Matrix metalloproteinases and their inhibitors. Farmakokinetika i farmakodinamika. – Pharmacokinetics and pharmacodynamics. 2019;2:3-16. https://doi.org/10.24411/2587-7836-2019-10040
16. Cui N., Hu M., Khalil R. A. Biochemical and biological attributes of matrix metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017;147:1-73. https://doi.org/10.1016/bs.pmbts.2017.02.005
17. Madzharova E., Kastl P., Sabino F., Keller U. A. D. Post-translational modification-dependent activity of matrix metalloproteinases. Int. J. Mol. Sci. 2019;20(12):3077. https://doi.org/10.3390/ijms20123077
18. Roderfeld M. Matrix metalloproteinase functions in hepatic injury and fibrosis. Matrix Biol. 2018;68-69:452-462. https://doi.org/10.1016/j.matbio.2017.11.011
19. Attallah A., El-Far M., Malak C. A. A., Omran M. M., Farid K. [et al.] Fibro-check: A combination of direct and indirect markers for liver fibrosis staging in chronic hepatitis C patients. Ann. Hepatol. 2015;14(2):225-233.
20. Ando W., Yokomori H., Tsutsui N., Yamanouchi E., Suzuki Y. [et al.] Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis. Clin. Mol. Hepatol. 2018;24(1):61-76. https://doi.org/10.3350/cmh.2017.0030
21. Prystupa A., Szpetnar M., Boguszewska-Czubara A., Grzybowski A., Sak J. [et al.] Activity of MMP1 and MMP13 and amino acid metabolism in patients with alcoholic liver cirrhosis. Medical Science Monitor. 2015;21:1008-1014. https://doi.org/10.12659/MSM.892312
22. Moskalenko M. I., Ponоmarenko I. V., Polоnikov A. V., Churnоsov M. I. Polymоrphic lоcus RS17577 оf MMP9 gеne is assоciated with еssential hypеrtension in mеn. Medical News of Nоrth Cauсasus. 2020;15(1):39-43. https://doi.org/10.14300/mnnc.2020.15008
23. Itaba N., Kono Y., Watanabe K., Yokobata T., Oka H. [et al.] Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets. Sci. Rep. 2019;9(1):6841. https://doi.org/10.1038/s41598-019-43298-0
24. Zhou Z., Ma X., Wang F.-M., Sun L., Zhang G. A Matrix metalloproteinase-1 polymorphism, MMP1–1607 (1G>2G), is associated with increased cancer risk: a meta-analysis including 21,327 patients. Dis. Markers. 2018;2018:7565834. https://doi.org/10.1155/2018/7565834
25. Powell B., Malaspina D. C., Szleifer I., Dhaher Y. Effect of collagenase–gelatinase ratio on the mechanical properties of a collagen fibril: a combined Monte Carlo-molecular dynamics study. Biomech. Model. Mechanobiol. 2019;18(6):1809-1819. https://doi.org/10.1007/s10237-019-01178-6
26. Prystupa A., Boguszewska-Czubara A., Bojarska-Junak A., Toru´n-Jurkowska A., Roli´nski J. [et al.] Activity of MMP-2, MMP-8 and MMP-9 in serum as a marker of progression of alcoholic liver disease in people from Lublin Region, eastern Poland. Ann. Agric. Environ. Med. 2015;22(2):325-328. https://doi.org/10.5604/12321966.1152088
27. Calabro S. R., Maczurek A. E., Morgan A. J., Tu T., Wen V. W. [et al.] Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis. PLoS ONE. 2014;9(7):e90571. https://doi.org/10.1371/journal.pone.0090571
28. Kato H., Kuriyama N., Duarte S., Clavien P.-A., Busuttil R. W. [et al.] MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury. J. Hepatol. 2014;60(5):1032-1039. https://doi.org/10.1016/j.jhep.2013.12.022
29. Li Y., Liu F., Ding F., Chen P., Tang M. Inhibition of liver fibrosis using vitamin A-coupled liposomes to deliver matrix metalloproteinase-2 siRNA in vitro. Mol. Med. Rep. 2015;12(3):3453-3461. https://doi.org/10.3892/mmr.2015.3842
30. Lu C., Zou Y., Liu Y., Niu Y. Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: involvement of Nrf2 antioxidant system. Toxicol. Appl. Pharmacol. 2017;318:69-78. https://doi.org/10.1016/j.taap.2017.01.008
31. Irvine K. M., Wockner L. F., Hoffmann I., Horsfall L. U., Fagan K. J. [et al.]. Multiplex serum protein analysis identifies novel biomarkers of advanced fibrosis in patients with chronic liver disease with the potential to improve diagnostic accuracy of established biomarkers. PLoS One. 2016;11(11):e0167001. https://doi.org/10.1371/journal.pone.0167001
32. Kerola A., Lampela H., Lohi J., Heikkilä P., Mutanen A. [et al.] Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia. J. Pathol. Clin. Res. 2016;2(3):187-198. https://doi.org/10.1002/cjp2.50
33. Harpavat S. MMP-7: the next best serum biomarker for biliary atresia? J. Pediatr. 2019;208:8-9. https://doi.org/10.1016/j.jpeds.2019.01.026
34. Wu J.-F., Jeng Y.-M., Chen H.-L., Ni Y.-H., Hsu H.-Y. [et al.] Quantification of serum matrix metallopeptide 7 levels may assist in the diagnosis and predict the outcome for patients with biliary atresia. J. Pediatr. 2019;208:30-37.e1. https://doi.org/10.1016/j.jpeds.2018.12.006
35. Giannandrea M., Parks W. C. Diverse functions of matrix metalloproteinases during fibrosis. Dis. Model. Mech. 2014;7(2):193-203. https://doi.org/10.1242/dmm.012062
36. Baig M. S., Yaqoob U., Cao S., Saqib U., Shah V. H. Non-canonical role of matrix metalloprotease (MMP) in activation and migration of hepatic stellate cells (HSCs). Life Sci. 2016;155:155-160. https://doi.org/10.1016/j.lfs.2016.04.031
37. Qin G., Luo M., Chen J., Dang Y., Chen G. [et al.] Reciprocal activation between MMP-8 and TGF-1 stimulate EMT and malignant progression of hepatocellular carcinoma. Cancer Lett. 2016;374(1):85-95. https://doi.org/10.1016/j.canlet.2016.02.001
38. Liu J., Li J., Fu W., Tang J., Feng X. [et al.] Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation. Drug Des. Dev. Ther. 2015;9:5655-5667. https://doi.org/10.2147/DDDT.S92481
39. Medeiros T., Saraiva G. N., Moraes L. A., Gomes A. C., Lacerda G. S. [et al.] Liver fibrosis improvement in chronic hepatitis C after direct acting-antivirals is accompanied by reduced profibrogenic biomarkers-a role for MMP-9/TIMP-1. Dig. Liver Dis. 2020;52(10):1170-1177. https://doi.org/10.1016/j.dld.2020.05.004
40. Wang X., Maretti-Mira A. C., Wang L., Deleve L. D. Liver-selective MMP-9 inhibition in the rat eliminates ischemia-reperfusion injury and accelerates liver regeneration. Hepatology. 2019;69(1):314-328. https://doi.org/10.1002/hep.30169
41. Feng M., Ding J., Wang M., Zhang J., Zhu X. [et al.] Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution. Int. J. Biol. Sci. 2018;14(9):1033-1040. https://doi.org/10.7150/ijbs.25589
42. Lachowski D., Cortes E., Rice A., Pinato D., Rombouts K. [et al.] Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis. Sci. Rep. 2019;9(1):7299. https://doi.org/10.1038/s41598-019-43759-6
43. Hori T., Uemoto S., Walden L.B., Chen F., Baine A.-M. T. [et al.] Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: a pilot study in mice. Hepatol. Res. 2014;44(6):651-662. https://doi.org/10.1111/hepr.12161
44. Garcia-Irigoyen O., Carotti S., Latasa M. U., Uriarte I., Fernandez-Barrena M. G. [et al.] A. Matrix metalloproteinase-10 expression is induced during hepatic injury and plays a fundamental role in liver tissue repair. Liver Int. 2014;34(7):e257-e270. https://doi.org/10.1111/liv.12337
45. García-Irigoyen O., Latasa M. U., Carotti S., Uriarte I., Elizalde M. [et al.] Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis. Hepatology. 2015;62(1):166-178. https://doi.org/10.1002/hep.27798
46. Wang B., Hsu C.-J., Lee H.-L., Chou C.-H., Su C.-M. [et al.] Impact of matrix metalloproteinase-11 gene polymorphisms upon the development and progression of hepatocellular carcinoma. Int. J. Med Sci. 2018;15(6):653-658. https://doi.org/10.7150/ijms.23733
47. Dali-Youcef N., Hnia K., Blaise S., Messaddeq N., Blanc S. [et al.] Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch. Sci. Rep. 2016;6:25140. https://doi.org/10.1038/srep25140
48. George J., Tsutsumi M., Tsuchishima M. MMP-13 deletion decreases profibrogenic molecules and attenuates N-nitrosodimethylamine-induced liver injury and fibrosis in mice. J. Cell. Mol. Med. 2017;21(12):3821-3835. https://doi.org/10.1111/jcmm.13304
49. Załuska W., Prystupa A., Szpetnar M., Boguszewska-Czubara A., Grzybowski A., Sak J. Activity of MMP1 and MMP13 and amino acid metabolism in patients with alcoholic liver cirrhosis. Med Sci. Monit. 2015;21:1008-1014. https://doi.org/10.12659/MSM.892312
50. Jin D., Tao J., Li D., Wang Y., Li L. [et al.] Golgi protein 73 activation of MMP-13 promotes hepatocellular carcinoma cell invasion. Oncotarget. 2015;6(32):33523-33533. https://doi.org/10.18632/oncotarget.5590
51. Zhang H. A., Yan H. Q., Wang F., Wang Y. Y., Jiang Y. N. [et al.] TIPE2 inhibits TNF-α-induced hepatocellular carcinoma cell metastasis via Erk1/2 downregulation and NF-κB activation. Int. J. Oncol. 2015;46(1):254-264. https://doi.org/10.3892/ijo.2014.2725
52. Itoh Y. Membrane-type matrix metalloproteinases: their functions and regulations. Matrix Biol. 2015;44:207-223. https://doi.org/10.1016/j.matbio.2015.03.004
53. Scheau C., Badarau I. A., Costache R. S., Caruntu C., Mihai G. L. [et al.] The role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma. Anal. Cell. Pathol. 2019:9423907. https://doi.org/10.1155/2019/9423907
54. Tsai H.-F., Trubelja A., Shen A. Q., Bao G. Tumour-ona-chip: microfluidic models of tumour morphology, growth and microenvironment. J. R. Soc. Interface.2017;14(131):20170137. https://doi.org/10.1098/rsif.2017.0137
55. Stoyanov E., Ludwig G., Mizrahi L., Olam D., SchnitzerPerlman T. [et al.] Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis. Oncotarget. 2015;6(13):11047-11060. https://doi.org/10.18632/oncotarget.3567
56. Soria-Valles C., Gutiérrez-Fernández A., Osorio F. G., Carrero D., Ferrando A. A. [et al.] MMP-25 metalloprotease regulates innate immune response through NF-FB signaling. J. Immunol. 2016;197(1):296-302. https://doi.org/10.4049/jimmunol.1600094
57. Zhou J., Zheng X., Feng M., Mo Z., Shan Y. [et al.] Upregulated MMP28 in hepatocellular carcinoma promotes metastasis via notch3 signaling and predicts unfavorable prognosis. Int. J. Boil. Sci. 2019;15(4):812-825. https://doi.org/10.7150/ijbs.31335
58. Fields G. B. The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells. 2019;8(9):984. https://doi.org/10.3390/cells8090984
59. Freitas-Rodríguez S., Folgueras A., Lopez-Otin C. The role of matrix metalloproteinases in aging: tissue remodeling and beyond. Biochim. Biophys. Acta Mol. Cell. Res. 2017;1864:2015-2025. https://doi.org/10.1016/j.bbamcr.2017.05.007

Keywords: matrix metalloproteinases, liver diseases, liver fibrosis

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Pyatigorsk State Research Institute of Balneotherapeutics
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