Matrix metalloproteinase 9 induces keratinocyte apoptosis through FasL/Fas pathway in diabetic wound

• Updated on: 2019-09-23
• Read original article here

pp 1–10 | Cite as
Matrix metalloproteinase 9 induces keratinocyte apoptosis through FasL/Fas pathway in diabetic wound
Authors
10 Downloads
Abstract
Apoptosis is a mechanism to remove unwanted cells in the tissue. In diabetic wound, which is characterized by delayed healing process, excessive apoptosis is documented and plays a crucial role. Matrix metalloproteinase 9 (MMP9), which is elevated in non-healed diabetic wound, is necessary for healing process but its abnormality resulted in a delayed healing. The classical function of MMP9 is the degradation of extracellular matrix (ECM). However, there is some literature evidence that MMP9 triggers cell apoptosis. Whether the excessive MMP9 contributes to epidermis cell apoptosis in delayed healing diabetic wound and the underlying mechanisms is not clear. In this study, we aimed to explore whether MMP9 induced keratinocyte apoptosis and investigate the plausible mechanisms. Our in vitro study showed that advanced glycation end products (AGEs) induced keratinocyte apoptosis and enhanced MMP9 level. Besides, MMP9, both intra-cellular expressions and extra-cellular supplement, promoted cell apoptosis. Further, MMP9 resulted in an increased expression of FasL, other than Fas and p53. These findings identified a novel effect that MMP9 exerted in delayed diabetic wound healing, owing to a pro-apoptotic effect on keratinocyte, which was mediated by an increase of FasL expression. This study increases understanding of elevated MMP9 which is involved in diabetic wound repair and offers some insights into novel future therapies.
Keywords
Advanced glycation end products Matrix metalloproteinase 9 Apoptosis Signaling pathway 
Ying Liang and Chuan Yang have contributed equally to this work and should be regarded as co-first authors.
Meng Ren and Li Yan have contributed equally to this work and should be regarded as co-corresponding authors.
Electronic supplementary material
The online version of this article (  https://doi.org/10.1007/s10495-019-01536-w ) contains supplementary material, which is available to authorized users.
This is a preview of subscription content, log in to check access.
Notes
This study was funded by the National Natural Science Foundation of China (81770827, 81471034).
Compliance with ethical standards
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary material
10495_2019_1536_MOESM1_ESM.tif (19.4 mb)
Supplemental figure (not mentioned in the article, just to identify keratinocyte). a. Human keratinocytes culture (200×). b. Keratin secretion observed by microscope. (A). Keratin images in normal microscope (100×). (B). Keratin images in immunofluorescence microscopy (100×). (C). Cell nucleus images in immunofluorescence microscopy (100×). (TIF 19888 KB)
References
1.
Singh N, Armstrong DG, Lipsky BA (2005) Preventing foot ulcers in patients with diabetes. JAMA 293(2):217–228 CrossRef Google Scholar
2.
Muller IS, de Grauw WJ, van Gerwen WH et al (2002) Foot ulceration and lower limb amputation in type 2 diabetic patients in dutch primary health care. Diabetes Care 25(3):570–574 CrossRef Google Scholar
3.
American Diabetes Association (2013) Economic costs of diabetes in the U.S. in 2012. Diabetes Care 36(4):1033–1046 CrossRef Google Scholar
4.
Rai NK, Tripathi K, Sharma D et al (2005) Apoptosis: a basic physiologic process in wound healing. Int J Low Extrem Wounds 4(3):138–144 CrossRef Google Scholar
5.
Greenhalgh DG (1998) The role of apoptosis in wound healing. Int J Biochem Cell Biol 30(9):1019–1030 CrossRef Google Scholar
6.
Edwards M, Jones D (2001) Programmed cell death in human acute cutaneous wounds. J Cutan Pathol 28:151–155 CrossRef Google Scholar
7.
Tuan TL, NichterL S (1998) The molecular basis of keloid and hypertrophic scar formation. Mol Med Today 4:19–24 CrossRef Google Scholar
8.
Kane CD, Greenhalgh DG (2000) Expression and localization of p53 and bcl-2 in healing wounds in diabetic and nondiabetic mice. Wound Repair Regen 8(1):45–58 CrossRef Google Scholar
9.
Darby IA, Bisucci T, Hewitson TD et al (1997) Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice. Int J Biochem Cell Biol 29(1):191–200 CrossRef Google Scholar
10.
Bhan S, Mitra R, Arya AK et al (2013) A study on evaluation of apoptosis and expression of bcl-2-related marker in wound healing of streptozotocin-induced diabetic rats. ISRN Dermatol 2013:739054 CrossRef Google Scholar
11.
Ponugoti B, Dong G, Graves DT (2012) Role of forkhead transcription factors in diabetes-induced oxidative stress. Exp Diabetes Res 2012:939751 CrossRef Google Scholar
12.
Wang XJ, Han G, Owens P et al (2006) Role of TGF beta-mediated inflammation in cutaneous wound healing. J Invest Dermatol Symp Proc 11(1):112–117 CrossRef Google Scholar
13.
Maas-Szabowski N, Starker A, Fusenig NE (2003) Epidermal tissue regeneration and stromal interaction in HaCaT cells is initiated by TGF-alpha. J Cell Sci 116(pt 14):2937–2948 CrossRef Google Scholar
14.
Bandyopadhyay B, Fan J, Guan S et al (2006) A “traffic control” role for TGFbeta3: orchestrating dermal and epidermal cell motility during wound healing. J Cell Biol 172(7):1093–1105 CrossRef Google Scholar
15.
Kawai K, Kageyama A, Tsumano T et al (2008) Effects of adiponectin on growth and differentiation of human keratinocytes-implication of impaired wound healing in diabetes. Biochem Biophys Res Commun 374(2):269–273 CrossRef Google Scholar
16.
Hu SC, Lan CE (2016) High-glucose environment disturbs the physiologic functions of keratinocytes: focusing on diabetic wound healing. J Dermatol Sci 84(2):121–127 CrossRef Google Scholar
17.
Ayuk SM, Abrahamse H, Houreld NN (2016) The role of matrix metalloproteinases in diabetic wound healing in relation to photobiomodulation. J Diabetes Res 2016:2897656 CrossRef Google Scholar
18.
López-López N, González-Curiel I, Treviño-Santa Cruz MB et al (2014) Expression and vitamin D-mediated regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy skin and in diabetic foot ulcers. Arch Dermatol Res 306(9):809–821 CrossRef Google Scholar
19.
Ladwig GP, Robson MC, Liu R et al (2002) Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Rep Reg 10:26–37 CrossRef Google Scholar
20.
Muller M, Trocme C, Lardy B et al (2008) Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing. Diabet Med 25(4):419–426 CrossRef Google Scholar
21.
Liu Y, Min D, Bolton T et al (2009) Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care 32(1):117–119 CrossRef Google Scholar
22.
Hoehna Y, Uckermann O, Luksch H et al (2012) Matrix metalloproteinase 9 regulates cell death following pilocarpine-induced seizures in the developing brain. Neurobiol Dis 48(3):339–347 CrossRef Google Scholar
23.
Manabe S, Gu Z, Lipton SA (2005) Activation of matrix metalloproteinase-9 via neuronal nitric oxide synthase contributes to NMDA-induced retinal ganglion cell death. Invest Ophthalmol Vis Sci 46(12):4747–4753 CrossRef Google Scholar
24.
Tran ED, DeLano FA, Schmid-Schonbein GW (2010) Enhanced matrix metalloproteinase activity in the spontaneously hypertensive rat: VEGFR-2 cleavage, endothelial apoptosis, and capillary rarefaction. J Vasc Res 47(5):423–431 CrossRef Google Scholar
25.
Xu J, Liu H, Wu Y et al (2011) Proapoptotic effect of metalloproteinase 9 secreted by trophoblasts on endothelial cells. J Obstet Gynaecol Res 37(3):187–194 CrossRef Google Scholar
26.
Bhagavathula N, Nerusu KC, Lal A et al (2004) Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes. J Invest Dermatol 122(1):130–139 CrossRef Google Scholar
27.
O’Toole EA, van Koningsveld R, Chen M et al (2008) Hypoxia induces epidermal keratinocyte matrix metalloproteinase-9 secretion via the protein kinase C pathway. J Cell Physiol 214(1):47–55 CrossRef Google Scholar
28.
Zhu P, Yang C, Chen LH et al (2011) Impairment of human keratinocyte mobility and proliferation by advanced glycation end products-modified BSA. Arch Dermatol Res 303(5):339–350 CrossRef Google Scholar
29.
Long M, Rojo de la Vega M, Wen Q et al (2016) An essential role of NRF2 in diabetic wound healing. Diabetes 65(3):780–793 CrossRef Google Scholar
30.
Hozzein WN, Badr G, Al Ghamdi AA et al (2015) Topical application of propolis enhances cutaneous wound healing by promoting TGF-beta/Smad-mediated collagen production in a streptozotocin-induced type I diabetic mouse model. Cell Physiol Biochem 37(3):940–954 CrossRef Google Scholar
31.
Dinh T, Tecilazich F, Kafanas A et al (2012) Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes 61(11):2937–2947 CrossRef Google Scholar
32.
Lobmann R, Ambrosch A, Schultz G et al (2002) Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 45(7):1011–1016 CrossRef Google Scholar
33.
Reiss MJ, Han YP, Garcia E, Goldberg M et al (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery 147(2):295–302 CrossRef Google Scholar
34.
Mannello F, Luchetti F, Falcieri E et al (2005) Multiple roles of matrix metalloproteinases during apoptosis. Apoptosis 10(1):19–24 CrossRef Google Scholar
35.
Kowluru RA (2010) Role of matrix metalloproteinase-9 in the development of diabetic retinopathy and its regulation by H-Ras. Invest Ophthalmol Vis Sci 51(8):4320–4326 CrossRef Google Scholar
36.
Sung PH, Chua S, Chen KH et al (2018) Role of double knockdown of tPA and MMP-9 on regulating the left ventricular function and remodeling followed by transverse aortic constriction-induced hypertrophic cardiomyopathy in mice. Am J Transl Res 10(9):2781–2795 Google Scholar
37.
Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92(8):827–839 CrossRef Google Scholar
38.
Arya AK, Tripathi R, Kumar S et al (2014) Recent advances on the association of apoptosis in chronic non healing diabetic wound. World J Diabetes 5(6):756–762 CrossRef Google Scholar
39.
Hoke GD, Ramos C, Hoke NN et al (2016) Atypical diabetic foot ulcer keratinocyte protein signaling correlates with impaired wound healing. J Diabetes Res 2016:1586927 CrossRef Google Scholar
40.
Gutierrez-Steil C, Wrone-Smith T, Sun X, Krueger JG et al (1998) Sunlight-induced basal cell carcinoma tumor cells and ultraviolet-B-irradiated psoriatic plaques express Fas ligand (CD95L). J Clin Invest 101(1):33–39 CrossRef Google Scholar
41.
Berthou C, Michel L, Soulie A et al (1997) Acquisition of granzyme B and Fas ligand proteins by human keratinocytes contributes to epidermal cell defense. J Immunol 159(11):5293–5300 Google Scholar
42.
Arnold R, Seifert M, Asadullah K, Volk HD (1999) Crosstalk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction: modulation by cytokines. J Immunol 162(12):7140–7147 Google Scholar
43.
Leverkus M, Yaar M, Gilchrest BA (1997) Fas/Fas ligand interaction contributes to UV-induced apoptosis in human keratinocytes. Exp Cell Res 232(2):255–262 CrossRef Google Scholar
44.
Hill LL, Ouhtit A, Loughlin SM et al (1999) Fas ligand: a sensor for DNA damage critical in skin cancer etiology. Science 285(5429):898–900 CrossRef Google Scholar
45.
Viard-Leveuqle I, Bullani RR, Meda P et al (2003) Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions. J Biol Chem 278(18):16183–16188 CrossRef Google Scholar
46.
Galkowska H, Olszewsk WL, Wojewodzka U et al (2003) Expression of apoptosis and cell cycle-related proteins in epidermis of venous leg and diabetic foot ulcers. Surgery 134(2):213–220 CrossRef Google Scholar
Copyright information
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Authors and Affiliations