The short-term effects of Conbercept intravitreal injection on matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2 expression in the aqueous humor of eyes with proliferative diabetic retinopathy._Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Wei , Zhu Kai , Jia Wen , Zhang Rui , Li Xuran ,  Gu Yonghao

Department of Ophthalmology, The First Affiliated Hospital of University of Science and Technology, Anhui Province Hospital , Hefei 230001, China;

Corresponding author：

Gu Yonghao, Email: guyh@ustc.edu.cn

Keywords：

Diabetic retinopathy; Vascular endothelial growth factor; Matrix metalloproteinase; Tissue inhibitor of metalloproteinase; Conbercept

DOI：

10.3760/cma.j.cn511434-20240902-0328

Video：

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Objective To observe and analyze the short-term effects of intravitreal injection of Conbercept (IVC) on the expression levels of matrix metalloproteinase (MMP)-2 and MMP inhibitor-2 (TIMP-2) in the aqueous humor of eyes with proliferative diabetic retinopathy (PDR). Methods A prospective clinical study. From March 2024 to June 2024, 30 consecutive patients with 30 eyes with PDR (PDR group) undergoing IVC combined with pars plana vitrectomy (PPV) at Department of Ophthalmology of The First Affiliated Hospital of University of Science and Technology were included in the study, along with 20 patients with 20 eyes undergoing cataract surgery (control group) during the same period. In the PDR group, IVC treatment was performed 3 to 7 days before PPV, and 0.05-0.10 ml aqueous humor was collected before IVC and before PPV. In the control group, 0.05-0.10 ml aqueous humor was collected before cataract surgery. The levels of vascular endothelial growth factor (VEGF), MMP-2, and TIMP-2 in the aqueous humor were measured using enzyme-linked immunosorbent assay. For normally distributed data, independent samples t-test were used for comparison between two groups; for non-normally distributed data, the Mann-Whitney U test was used. Correlation analysis was performed using Pearson's correlation coefficient. Results There were no statistically significant differences in age (Z=－1.810) and gender composition (χ²=3.450) between the PDR group and the control group (P＞0.05). Before IVC, VEGF and MMP-2 expression levels were (0.23±0.10), (2.11±1.32) ng/ml and (0.12±0.03), (0.53±0.26) ng/ml in patients' aqueous fluid in PDR group and control group, respectively. The expression level of TIMP-2 and the ratio of MMP-2/TIMP-2 were (0.99±0.26), (1.76±0.11) ng/ml and 2.04 (1.19, 2.98), 0.36 (0.15, 0.39), respectively. Compared with the control group, the expression levels of VEGF and MMP-2 in aqueous humor in PDR group (t=－5.030, －5.260) and the ratio of MMP-2/TIMP-2 (Z=－5.740) were significantly increased, with statistical significance (P＜0.01). The expression level of TIMP-2 was significantly lower than that of control group, the difference was statistically significant (t=12.120, P＜0.01). After IVC, the expression levels of VEGF and MMP-2 in aqueous humor of PDR patients were (0.13±0.03) and (2.11±1.32) ng/ml, respectively. The expression level of TIMP-2 and the ratio of MMP-2/ TIMP-2 were (0.95±0.28) ng/ml and 1.57 (1.02, 3.13), respectively. Compared with before IVC, the expression level of VEGF in aqueous humor in PDR group after IVC was significantly decreased, and the difference was statistically significant (t=6.080, P＜0.01). The expression levels of MMP-2 (t=1.220), TIMP-2 (t=0.290) and the ratio of MMP-2/TIMP-2 (Z=－0.260) were not significantly different (P=0.270, 0.780, 0.800). After IVC, there was no significant difference in VEGF expression level between PDR group and control group (t=－1.200, P=0.240). The expression level of MMP-2 was still significantly increased (t=－5.880), the expression level of TIMP-2 was still significantly decreased (t=11.520), and the ratio of MMP-2/TIMP-2 was still significantly increased (Z=－5.780), with statistical significance (P＜0.01). Correlation analysis showed that VEGF was positively correlated with MMP-2 in aqueous humor of PDR patients before IVC (r=0.590, P＜0.01). Conclusions IVC can effectively reduce the level of VEGF in the aqueous humor of eyes with PDR in the short term, but it has no significant effect on the levels of MMP-2 and TIMP-2.

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17.	Chetty C, Lakka SS, Bhoopathi P, et al. MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells[J]. Int J Cancer, 2010, 127(5): 1081-1095. DOI: 10.1002/ijc.25134.
18.	Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: what is all the fuss about?[J]. Matrix Biol, 1997, 15(8-9): 519-526. DOI: 10.1016/s0945-053x(97)90026-3.
19.	Claesson-Welsh L, Welsh M. VEGFA and tumour angiogenesis[J]. J Intern Med, 2013, 273(2): 114-127. DOI: 10.1111/joim.12019.
20.	Qin Z, Balimunkwe RM, Quan T. Age-related reduction of dermal fibroblast size upregulates multiple matrix metalloproteinases as observed in aged human skin in vivo[J]. Br J Dermatol, 2017, 177(5): 1337-1348. DOI: 10.1111/bjd.15379.
21.	Lehmann GL, Ginsberg M, Nolan DJ, et al. Retinal pigment epithelium-secreted VEGF-A induces alpha-2-macroglobulin expression in endothelial cells[J/OL]. Cells, 2022, 11(19): 2975[2022- 09-24]. https://pubmed.ncbi.nlm.nih.gov/36230937/. DOI: 10.3390/cells11192975.
22.	Clark AW, Krekoski CA, Bou SS, et al. Increased gelatinase A (MMP-2) and gelatinase B (MMP- 9) activities in human brain after focal ischemia[J]. Neurosci Lett, 1997, 238(1-2): 53-56. DOI: 10.1016/s0304-3940(97)00859-8.
23.	Rodrigues M, Xin X, Jee K, et al. VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy[J]. Diabetes, 2013, 62(11): 3863-3873. DOI: 10.2337/db13-0014.
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25.	Wu W, Su Y, Hu C, et al. Hypoxia-induced scleral HIF-2α upregulation contributes to rises in MMP-2 expression and myopia development in mice[J]. Invest Ophthalmol Vis Sci, 2022, 63(8): 2. DOI: 10.1167/iovs.63.8.2.
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1. Ucgun NI, Zeki-Fikret C, Yildirim Z. Inflammation and diabetic retinopathy[J]. Mol Vis, 2020, 26: 718-721.
2. Yue T, Shi Y, Luo S, et al. The role of inflammation in immune system of diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications[J/OL]. Front Immunol, 2022, 13: 1055087[2022-12-13]. https://pubmed.ncbi.nlm.nih.gov/36582230/. DOI: 10.3389/fimmu.2022.1055087.
3. Uludag G, Hassan M, Matsumiya W, et al. Efficacy and safety of intravitreal anti-VEGF therapy in diabetic retinopathy: what we have learned and what should we learn further?[J]. Expert Opin Biol Ther, 2022, 22(10): 1275-1291. DOI: 10.1080/14712598.2022.2100694.
4. Caban M, Owczarek K, Lewandowska U. The role of metalloproteinases and their tissue inhibitors on ocular diseases: focusing on potential mechanisms[J/OL]. Int J Mol Sci, 2022, 23(8): 4256[2022-04-12]. https://pubmed.ncbi.nlm.nih.gov/35457074/. DOI: 10.3390/ijms23084256.
5. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases[J/OL]. Int J Mol Sci, 2020, 21(24): 9739[2020-12-20]. https://pubmed.ncbi.nlm.nih.gov/33419373/. DOI: 10.3390/ijms21249739.
6. 金明, 吴景天, 柏木贤治, 等. 糖尿病及非糖尿病视网膜病变患者玻璃体中基质金属蛋白酶的表达[J]. 中华眼底病杂志, 2001, 17(3): 195-197. DOI: 10.1007/s11670-001-0053-5.Jin M, Wu JT, Bai MXZ, et al. Matrix metalloproteinase in human diabetic and non-diabetic vitreous[J]. Chin J Ocul Fundus Dis, 2001, 17(3): 195-197. DOI: 10.1007/s11670-001-0053-5.
7. Ebrahem Q, Chaurasia SS, Vasanji A, et al. Cross-talk between vascular endothelial growth factor and matrix metalloproteinases in the induction of neovascularization in vivo[J]. Am J Pathol, 2010, 176(1): 496-503. DOI: 10.2353/ajpath.2010.080642.
8. 中华医学会糖尿病学分会视网膜病变学组. 糖尿病相关眼病防治多学科中国专家共识(2021年版)[J]. 中华糖尿病杂志, 2021, 13(11): 1026-1042. DOI: 10.3760/cma.j.cn115791-20211006-00534.Diabetic Retinopathy Group of Chinese Diabetes Society. Chinese multidisciplinary expert consensus on the prevention and treatment of diabetic eye disease(2021 edition)[J]. Chin J Diabetes Mellitus, 2021, 13(11): 1026-1042. DOI: 10.3760/cma.j.cn115791-20211006-00534.
9. 中华医学会眼科学分会白内障及屈光手术学组. 中国成人白内障摘除手术指南(2023年)[J]. 中华眼科杂志, 2023, 59(12): 977-987. DOI: 10.3760/cma.j.cn112142-20230829-00066.Cataract and Refractive Surgery Group of Chinese Ophthalmological Society. Chinese guideline for cataract surgery in adults (2023)[J]. Chin J Ophthalmol, 2023, 59(12): 977-987. DOI: 10.3760/cma.j.cn112142-20230829-00066.
10. Wang Q, Li T, Wu Z, et al. Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable anti-angiogenesis effect in vivo[J/OL]. PLoS One, 2013, 8(8): e70544[2013-08-12]. https://pubmed.ncbi.nlm.nih.gov/23950958/. DOI: 10.1371/journal.pone.0070544.
11. 罗金秀, 胡仔仲, 刘庆淮, 等. 抗VEGF辅助治疗增殖性糖尿病视网膜病变对眼内炎症因子水平的影响[J]. 国际眼科杂志, 2023, 23(5): 827-832. DOI: 10.3980/j.issn.1672-5123.2023.5.22.Luo JX, Hu ZZ, Liu QH, et al. Effect of anti-vascular endothelial growth factor therapy on intraocular inflammatory cytokine levels in the treatment of proliferative diabetic retinopathy[J]. Int Eye Sci, 2023, 23(5): 827-832. DOI: 10.3980/j.issn.1672-5123.2023.5.22.
12. Wang Q, Cai H, Xu D, et al. Pars plana vitrectomy assisted by intravitreal injection of conbercept enhances the therapeutic effect and quality of life in patients with severe proliferative diabetic retinopathy[J]. Am J Transl Res, 2022, 14(2): 1324-1331.
13. Wang W, Qu C, Yan H. Network meta-analysis of intravitreal conbercept as an adjuvant to vitrectomy for proliferative diabetic retinopathy[J/OL]. Front Endocrinol (Lausanne), 2023, 14: 1098165[2023-02-22]. https://pubmed.ncbi.nlm.nih.gov/36896181/. DOI: 10.3389/fendo.2023.1098165.
14. Yang Z, Di Y, Ye J, et al. Comparison of the adjuvant effect of conbercept intravitreal injection at different times before vitrectomy for proliferative diabetic retinopathy[J/OL]. Front Endocrinol (Lausanne), 2023, 14: 1171628[2023-05-26]. https://pubmed.ncbi.nlm.nih.gov/37305048/. DOI: 10.3389/fendo.2023.1171628.
15. Li B, Li MD, Ye JJ, et al. Vascular endothelial growth factor concentration in vitreous humor of patients with severe proliferative diabetic retinopathy after intravitreal injection of conbercept as an adjunctive therapy for vitrectomy[J]. Chin Med J (Engl), 2020, 133(6): 664-669. DOI: 10.1097/CM9.0000000000000687.
16. Rundhaug JE. Matrix metalloproteinases and angiogenesis[J]. J Cell Mol Med, 2005, 9(2): 267-285. DOI: 10.1111/j.1582-4934.2005.tb00355.x.
17. Chetty C, Lakka SS, Bhoopathi P, et al. MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells[J]. Int J Cancer, 2010, 127(5): 1081-1095. DOI: 10.1002/ijc.25134.
18. Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: what is all the fuss about?[J]. Matrix Biol, 1997, 15(8-9): 519-526. DOI: 10.1016/s0945-053x(97)90026-3.
19. Claesson-Welsh L, Welsh M. VEGFA and tumour angiogenesis[J]. J Intern Med, 2013, 273(2): 114-127. DOI: 10.1111/joim.12019.
20. Qin Z, Balimunkwe RM, Quan T. Age-related reduction of dermal fibroblast size upregulates multiple matrix metalloproteinases as observed in aged human skin in vivo[J]. Br J Dermatol, 2017, 177(5): 1337-1348. DOI: 10.1111/bjd.15379.
21. Lehmann GL, Ginsberg M, Nolan DJ, et al. Retinal pigment epithelium-secreted VEGF-A induces alpha-2-macroglobulin expression in endothelial cells[J/OL]. Cells, 2022, 11(19): 2975[2022- 09-24]. https://pubmed.ncbi.nlm.nih.gov/36230937/. DOI: 10.3390/cells11192975.
22. Clark AW, Krekoski CA, Bou SS, et al. Increased gelatinase A (MMP-2) and gelatinase B (MMP- 9) activities in human brain after focal ischemia[J]. Neurosci Lett, 1997, 238(1-2): 53-56. DOI: 10.1016/s0304-3940(97)00859-8.
23. Rodrigues M, Xin X, Jee K, et al. VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy[J]. Diabetes, 2013, 62(11): 3863-3873. DOI: 10.2337/db13-0014.
24. Hua Y, Zhang W, Xie Z, et al. MMP-2 is mainly expressed in arterioles and contributes to cerebral vascular remodeling associated with TGF-β1 signaling[J]. J Mol Neurosci, 2016, 59(3): 317-325. DOI: 10.1007/s12031-015-0687-2.
25. Wu W, Su Y, Hu C, et al. Hypoxia-induced scleral HIF-2α upregulation contributes to rises in MMP-2 expression and myopia development in mice[J]. Invest Ophthalmol Vis Sci, 2022, 63(8): 2. DOI: 10.1167/iovs.63.8.2.
26. Shen Y, Gu J, Liu Z, et al. Inhibition of HIF-1α reduced blood brain barrier damage by regulating MMP-2 and VEGF during acute cerebral ischemia[J/OL]. Front Cell Neurosci, 2018, 12: 288[2018-09- 04]. https://pubmed.ncbi.nlm.nih.gov/30233326/. DOI: 10.3389/fncel.2018.00288.
27. 赖思艺, 邱心悦, 何建忠, 等. 益景汤调控MMPs/TIMPs相关分子拮抗高糖诱导的iBRB模型基底膜损害[J]. 国际眼科杂志, 2024, 24(9): 1387-1391. DOI: 10.3980/j.issn.1672-5123.2024.9.07.Lai SY, Qiu XY, He JZ, et al. Yijing Decoction regulates MMPs/TIMPs-related molecules to antagonize high glucose-induced basement membrane damage in iBRB mode[J]. Int Eye Sci, 2024, 24(9): 1387-1391. DOI: 10.3980/j.issn.1672-5123.2024.9.07.
28. Song S, Yu X, Zhang P, et al. Increased levels of cytokines in the aqueous humor correlate with the severity of diabetic retinopathy[J/OL]. J Diabetes Complications, 2020, 34(9): 107641[2020-05-30]. https://pubmed.ncbi.nlm.nih.gov/32605862/. DOI: 10.1016/j.jdiacomp.2020.107641.
29. 王桂云, 左玲, 李旭, 等. 基质金属蛋白酶-2、-9含量表达与孔源性视网膜脱离相关性研究[J]. 中国老年学杂志, 2006, 26(12): 1626-1627. DOI: 10.3969/j.issn.1005-9202.2006.12.014.Wang GY, Zuo L, Li X, et al. A study on the correlation between matrix metalloproteinase-2 and -9 expression levels and rhegmatogenous retinal detachment[J]. Chin J Gerontology, 2006, 26(12): 1626-1627. DOI: 10.3969/j.issn.1005-9202.2006.12.014.
30. 刘东宁. 基质金属蛋白酶在增殖性糖尿病视网膜病变增殖膜中的表达研究[D]. 沈阳: 中国医科大学, 2004.Liu DL. Study on the expression of matrix metalloproteinases in proliferative membranes of proliferative diabetic retinopathy[D]. Shenyang: China Medical University, 2004.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesThe short-term effects of Conbercept intravitreal injection on matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2 expression in the aqueous humor of eyes with proliferative diabetic retinopathy.

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