Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, Beijing, China.
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sci Rep. 2017 Sep 5;7(1):10565. doi: 10.1038/s41598-017-10999-3.
Keratinocyte migration is a key aspect of re-epithelialization during wound healing. Matrix metalloproteinase 9 (MMP9) contributes to this process and deficiencies in the MMP9 lead to impaired healing. Inappropriate expression of MMP9 also contributes to impaired re-epithelialization. Previously we demonstrated that FOXO1 was activated in wound healing but to higher levels in diabetic wounds. To address mechanisms of impaired re-epithelialization we examined MMP9 expression in vivo in full thickness dermal scalp wounds created in experimental K14.Cre .Foxo1 mice with lineage-specific Cre recombinase deletion of floxed FOXO1 and compared the results to control littermates. MMP9 was induced during wound healing but at a significantly higher level in diabetic compared to normal wounds. FOXO1 deletion substantially blocked this increase. By chromatin immunoprecipitation FOXO1 was shown to bind to the MMP9 promoter, FOXO1 overexpression increased MMP9 transcriptional activity and increased MMP9 expression stimulated by high glucose was blocked by FOXO1 deletion or FOXO1 knockdown. We also show for the first time that high glucose impairs keratinocyte migration by inducing high levels of MMP9 expression and establish that it involves FOXO1. Thus, FOXO1 drives high levels of MMP9 expression in diabetic wound healing, which represents a novel mechanism for impaired re-epithelization in diabetic wounds.
角质形成细胞迁移是伤口愈合过程中再上皮化的关键方面。基质金属蛋白酶 9（MMP9）有助于这一过程，而 MMP9 的缺乏会导致愈合受损。MMP9 的表达不当也会导致再上皮化受损。以前我们已经证明 FOXO1 在伤口愈合过程中被激活，但在糖尿病伤口中被激活到更高水平。为了解决再上皮化受损的机制，我们在实验性 K14.Cre 。Foxo1 小鼠的全厚真皮头皮伤口中体内检查了 MMP9 的表达，这些小鼠具有谱系特异性 Cre 重组酶缺失的 floxed FOXO1，并将结果与对照同窝仔鼠进行了比较。MMP9 在伤口愈合过程中被诱导，但在糖尿病伤口中比正常伤口高得多。FOXO1 缺失显著阻止了这种增加。通过染色质免疫沉淀，FOXO1 被证明与 MMP9 启动子结合，FOXO1 的过表达增加了 MMP9 的转录活性，高葡萄糖刺激的 MMP9 表达增加被 FOXO1 缺失或 FOXO1 敲低所阻断。我们还首次表明，高葡萄糖通过诱导高水平的 MMP9 表达来抑制角质形成细胞迁移，并证实这涉及 FOXO1。因此，FOXO1 在糖尿病伤口愈合中驱动 MMP9 表达水平升高，这代表了糖尿病伤口再上皮化受损的一种新机制。
