Matrix metalloproteinase-7 Induces Cellular Senescence By Activation Of p21 In Hyperglycemia
DOI:
https://doi.org/10.36320/ajb/v18.i2.24296Keywords:
Diabetes Mellitus, MMP7, p21, Hyperglycemia, HbA1c, Apoptosis, Gene Expression, Cellular Senescence, Extracellular Matrix, BiomarkersAbstract
Background: Matrix metalloproteinase-7 (MMP7) belongs to a major enzyme group of proteinases involved in extracellular matrix degradation and in controlling several biological processes such as cell division, apoptosis, and the development of Diabetes mellitus (DM) and its complications. High glucose can elicit a damaging DNA response, which ultimately leads to p21-dependent senescence. This study aimed to detect the effects of elevated glucose on increased expression levels of MMP7 and p21 in human sample, and to identify the correlation between expression levels of MMP7 and p21. Materials and methods: The influence of high glucose on serum levels of MMP7 and p21 was evaluated in 90 subjects, divided into two groups (diabetic patients, and healthy control). The key indicators of the male and female participants, in each group, were evaluated based on fasting blood sugar (FBS) and glycosylated hemoglobin (HbA1c). Finally the correlation among all study variables was established. Results: Expression levels of MMP7 and p21 were significantly higher in participants with diabetes and HbA1c, as compared to the healthy controls. A positive correlation was established between MMP7 and p21 within the study group. Conclusions: The elevated blood glucose enhanced the expression of MMP7 and p21 in diabetic patients, highlighting potential influence on disease progression. The positive correlation between MMP7 and p21 offers new insight into the role of MMP7 in promoting cellular apoptosis in diabetes.
Downloads
References
1- Van Deursen J M (2014). The role of senescent cells in ageing. Nature 509 (7501): 439–446. https://doi.org/10.1038/nature13193.
2- Liu J, Guo B, Liu Q, Zhu G, Wang Y et al (2024). Cellular senescence: a bridge between diabetes and microangiopathy. Biomolecules 14(11): 1361. https://doi.org/10.3390/biom14111361.
3- Zhang, Y., Zhao, Y., Liu, Y. Q., Fang, Y. P., Sun, L., Wei, S. Z., ... & Zhang, X. L. (2025). High glucose induces renal tubular epithelial cell senescence by inhibiting autophagic flux. Human Cell, 38(2), 43. https://doi.org/10.1007/s13577-024-01156-w.
4- Tan, S., Wu, W., Chen, Y., & Gao, H. (2025). High glucose induces senescence in synovial mesenchymal stem cells through mitochondrial dysfunction. BMC Oral Health, 25(1), 569. https://doi.org/10.1186/s12903-025-0569
5- Shi GJ, Shi GR, Zhou JY, Zhang WJ, Gao CY et al (2018). Involvement of growth factors in diabetes mellitus and its complications: A general review. Biomedicine & Pharmacotherapy 101: 510–527. https://doi.org/10.1016/j.biopha.2018.02.105.
6- Kita A, Saito Y, Miura N, Miyajima M, Yamamoto S et al (2022). Altered regulation of mesenchymal cell senescence in adipose tissue promotes pathological changes associated with diabetic wound healing. Communications Biology 5: 310 .https://doi.org/10.1038/s42003-022-03266-3.
7- Mahmoud AM, Ali MM (2021). High glucose and advanced glycation end products induce CD147-mediated MMP activity in human adipocytes. Cells 10(8): 2098. https://doi.org/10.3390/cells10082098
8- Al-Tamimi SQ, Salem WA, Ahmed HS, Younis HM, Al-Amiri RM et al (2025). Sodium bicarbonate toothpastes reduce metalloproteinase-8 and interleukin-1β levels in smokers and improve important salivary indexes. Opera Med Physiol 12(2): 5–12. https://doi.org/10.24412/2500-2295-2025-2-5-12
9- Lee YI, Choi S, Roh WS, Lee JH, Kim TG (2021). Cellular senescence and inflammaging in the skin microenvironment. International Journal of Molecular Sciences 22(8): 3849. https://doi.org/10.3390/ijms22083849
10 - Eleftheriadis T, Pissas G, Filippidis G, Efthymiadi M, Liakopoulos V et al (2022). Dapagliflozin prevents high-glucose-induced cellular senescence in renal tubular epithelial cells. International Journal of Molecular Sciences 23(24): 16107. https://doi.org/10.3390/ijms23241610
11- Elmitwalli O, Darwish R, Al Jabery L, Algahiny A, Roy S et al (2024). The emerging role of p21 in diabetes and related metabolic disorders. International Journal of Molecular Sciences 25(23): 13209. https://doi.org/10.3390/ijms252313209
12- Elwakiel A (2025). Targeting the hyperglycemic memory in diabetic kidney disease is therapeutically amendable (Doctoral dissertation, Universität Leipzig). Qucosa. https://nbn-resolving.org/urn:nbn:de:bsz:15-qucosa2-960075
13- Giri B, Dey S, Das T, Sarkar M, Banerjee J et al (2018). Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomedicine & Pharmacotherapy 107: 306–328. https://doi.org/10.1016/j.biopha.2018.07.157
14- Carette C, Czernichow S (2017). Harms and benefits of the haemoglobin glycation index (HGI). European Journal of Preventive Cardiology 24(13): 1402–1404. https://doi.org/10.1177/2047487317717821
15- Karp NA, Reavey N (2019). Sex bias in preclinical research and an exploration of how to change the status quo. British Journal of Pharmacology 176(21): 4107–4118. https://doi.org/10.1111/bph.14539
16- Panda CR, Mangaraj M, Panda SK, Kumari S, Nayak S et al (2025). Unravelling interplay of serum MMP-7 and TGF-β in diabetic nephropathy: A study from a tertiary centre in eastern India. Journal of Family Medicine and Primary Care 14(3): 997–1002. https://doi.org/10.4103/jfmpc.jfmpc_1158_24
17- Zhang Z, Li J, Yang L, Chen R, Yang R et al (2014). The cytotoxic role of intermittent high glucose on apoptosis and cell viability in pancreatic beta cells. Journal of Diabetes Research 2014(1): 712781. https://doi.org/10.1155/2014/712781
18- Garner E, Raj K (2008). Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle 7(3): 277–282. https://doi.org/10.4161/cc.7.3.5328
19- Zeidan-Chuliá F, Yilmaz D, Hakkinen L, Kononen E, Neves de Oliveira BH et al (2018). Matrix metalloproteinase-7 in periodontitis with type 2 diabetes mellitus. Journal of Periodontal Research 53(5): 916–923. https://doi.org/10.1111/jre.12583
20 - Murad NAA, Abdullah N, Kamaruddin MA, Abd Jalal N, Ismail N et al (2021). Discordance between fasting plasma glucose (FPG) and HbA1c in diagnosing diabetes and pre-diabetes in the Malaysian cohort. Journal of the ASEAN Federation of Endocrine Societies 36(2): 127. https://doi.org/10.15605/jafes.036.02.02
21- Burton DG, Faragher RG (2018). Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing. Biogerontology 19(6): 447–459. https://doi.org/10.1007/s10522-018-9763-7
22- Ameen AA, Suker DK (2022). MIR30a suppresses prostate cancer cells by increasing apoptosis and regulation of MMPs. Eurasian Medical Research Periodical 9: 26–34. https://doi.org/10.5281/zenodo.18395385
23- Garcia-Fernandez N, Jacobs-Cachá C, Mora-Gutiérrez JM, Vergara A, Orbe J et al (2020). Matrix metalloproteinases in diabetic kidney disease. Journal of Clinical Medicine 9(2): 472. https://doi.org/10.3390/jcm9020472
24- Sarangi R, Sahu D, Rout NK, Tripathy KP, Patra S et al (2024). Role of urinary matrix metalloproteinase-7 (MMP-7) as an early marker of renal dysfunction in diabetic individuals: A cross-sectional study. Cureus 16(8). https://doi.org/10.7759/cureus.66392
25- Chang M, Nguyen TT (2021). Strategy for treatment of infected diabetic foot ulcers. Accounts of Chemical Research 54(5): 1080–1093. https://doi.org/10.1021/acs.accounts.0c00864
26- Wu WC, Lee WJ, Lee TH, Chen SC, Chen CY (2020). Do different bariatric surgical procedures influence plasma levels of matrix metalloproteinase-2, -7, and -9 among patients with type 2 diabetes mellitus? World Journal of Diabetes 11(6): 252. https://doi.org/10.4239/wjd.v11.i6.252
27- Eckhardt BA, Rowsey JL, Thicke BS, Fraser DG, O’Grady KL et al (2020). Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes. JCI Insight 5(9): e135236. https://doi.org/10.1172/jci.insight.135236
28- Kitada K, Nakano D, Ohsaki H, Hitomi H, Minamino T et al (2014). Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. Journal of Diabetes and its Complications 28(5): 604–611. https://doi.org/10.1016/j.jdiacomp.2014.05.010
29- Wang L, Wang B, Gasek NS, Zhou Y, Cohn RL et al (2022). Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metabolism 34(1): 75–89. https://doi.org/10.1016/j.cmet.2021.11.002
30- Franko A, Berti L, Hennenlotter J, Rausch S, Scharpf MO et al (2020). Increased expressions of matrix metalloproteinases (MMPs) in prostate cancer tissues of men with type 2 diabetes. Biomedicines 8(11): 507. https://doi.org/10.3390/biomedicines8110507
31- Yan, J., Yi, Z., Chen, S., Zhao, R., Shi, J., Ding, S., ... & Wu, J. (2025). Dissecting Spatiotemporal Heterogeneity of Senescence Markers p16/p21 Across Tissues During Type 2 Diabetes Progression. Cell Biochemistry and Function, 43(10), e70127. https://doi.org/10.1002/cbf.70127.
32- Dutto I, Tillhon M, Cazzalini O, Stivala LA, Prosperi E (2015). Biology of the cell cycle inhibitor p21CDKN1A: Molecular mechanisms and relevance in chemical toxicology. Archives of Toxicology 89(2): 155–178. https://doi.org/10.1007/s00204-014-1430-4
33- Trimis G, Chatzistamou I, Politi K, Kiaris H, Papavassiliou AG (2008). Expression of p21WAF1/Cip1 in stromal fibroblasts of primary breast tumors. Human Molecular Genetics 17(22): 3596–3607. https://doi.org/10.1093/hmg/ddn252
34- Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J et al (2013). Programmed cell senescence during mammalian embryonic development. Cell 155(5): 1104–1118. https://doi.org/10.1016/j.cell.2013.10.019.
35- Tay VS, Devaraj S, Koh T, Ke G, Crasta KC et al (2019). Increased double strand breaks in diabetic β-cells with a p21 response that limits apoptosis. Scientific Reports 9(1): 19341. https://doi.org/10.1038/s41598-019-54554-8
36- Trentini A, Manfrinato MC, Castellazzi M, Bellini T (2022). Sex-related differences of matrix metalloproteinases (MMPs): New perspectives for these biomarkers in cardiovascular and neurological diseases. Journal of Personalized Medicine 12(8): 1196. https://doi.org/10.3390/jpm12081196
37- Broestl L, Warrington NM, Grandison L (2022). Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma. Communications Biology 5(1): 781. https://doi.org/10.1038/s42003-022-03743-9
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Azhar A. Ameen
This work is licensed under a Creative Commons Attribution 4.0 International License.
which allows users to copy, create extracts, abstracts, and new works from the Article, alter and revise the Article, and make commercial use of the Article (including reuse and/or resale of the Article by commercial entities), provided the user gives appropriate credit (with a link to the formal publication through the relevant DOI), provides a link to the license, indicates if changes were made and the licensor is not represented as endorsing the use made of the work.
