Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany, and Davila University of Medicine and Pharmacy, Bucharest, Romania.
Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Arthritis Rheumatol. 2020 Jan;72(1):137-149. doi: 10.1002/art.41058.
Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc).
Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6).
The expression of DPP-4 and the number of DPP-4-positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)-dependent manner. DPP-4-positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation.
DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.
二肽基肽酶 4（DPP-4）的表达鉴定了参与伤口愈合过程中瘢痕形成的真皮成纤维细胞谱系。然而，DDP-4 在组织纤维化中的作用尚不清楚。本研究旨在评估 DPP-4 作为一种治疗系统性硬皮病（SSc）患者纤维化的潜在靶点。
通过实时聚合酶链反应、免疫荧光和 Western blot 分析分析皮肤活检样本和成纤维细胞中 DPP-4 的表达。通过使用西他列汀和维达列汀过表达、敲低和药理学抑制 DPP4 来调节 DPP-4 的活性。在人真皮成纤维细胞和不同的 SSc 小鼠模型中分析 DPP4 抑制的影响（每组 n = 6）。
SSc 患者纤维化皮肤中 DPP-4 的表达和 DPP-4 阳性成纤维细胞的数量增加，这是 TGFβ 依赖性的。DPP-4 阳性成纤维细胞表达更高水平的肌成纤维细胞标志物和胶原蛋白（均 P < 0.001 与健康对照组相比）。DPP4 的过表达促进成纤维细胞激活，而药理学抑制或遗传失活 DPP4 通过干扰 TGFβ 诱导的 ERK 信号转导，减少增殖、迁移和收缩蛋白的表达以及胶原蛋白的释放（均 P < 0.001 与对照小鼠相比）。DPP4 敲除小鼠对博莱霉素诱导的皮肤和肺纤维化的敏感性降低（与野生型对照相比，P < 0.0001）。DPP4 抑制剂治疗促进了接受博莱霉素挑战和慢性移植物抗宿主病的小鼠的纤维化消退，并改善了 TSK1 小鼠的纤维化（与未治疗对照组相比，均 P < 0.001）。这些抗纤维化作用与炎症减少有关。
DPP-4 表征了一群激活的成纤维细胞，并表明 DPP-4 调节 SSc 患者纤维化皮肤中 TGFβ 诱导的成纤维细胞激活。在耐受良好的剂量下给予 DPP4 抑制剂可发挥强大的抗纤维化作用。由于 DPP4 抑制剂已用于治疗糖尿病，因此这些结果可能对治疗 SSc 患者的纤维化具有直接的转化意义。
