Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China.
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China.
Apoptosis. 2019 Aug;24(7-8):542-551. doi: 10.1007/s10495-019-01536-w.
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.
细胞凋亡是组织清除不需要的细胞的一种机制。在糖尿病伤口中，细胞凋亡过度被记录下来，并发挥着关键作用。糖尿病未愈合伤口中升高的基质金属蛋白酶 9（MMP9）对于愈合过程是必要的，但它的异常导致愈合延迟。MMP9 的经典功能是降解细胞外基质（ECM）。然而，有一些文献证据表明 MMP9 可引发细胞凋亡。过量的 MMP9 是否导致愈合延迟的糖尿病伤口中表皮细胞凋亡以及潜在的机制尚不清楚。在这项研究中，我们旨在探讨 MMP9 是否诱导角质形成细胞凋亡，并研究可能的机制。我们的体外研究表明，晚期糖基化终产物（AGEs）诱导角质形成细胞凋亡并增强 MMP9 水平。此外，MMP9 无论是在细胞内表达还是细胞外补充，都促进了细胞凋亡。此外，MMP9 导致 FasL 的表达增加，而 Fas 和 p53 的表达没有增加。这些发现确定了 MMP9 在延迟性糖尿病伤口愈合中发挥的新作用，这归因于 MMP9 对角质形成细胞的促凋亡作用，这种作用是通过 FasL 表达的增加介导的。这项研究增加了对参与糖尿病伤口修复的 MMP9 升高的理解，并为新的未来治疗方法提供了一些见解。
