Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
Scleroderma Program, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2022 Feb 24;13:814533. doi: 10.3389/fimmu.2022.814533. eCollection 2022.
Glycoprotein nonmetastatic melanoma protein B (GPNMB) is involved in various cell functions such as cell adhesion, migration, proliferation, and differentiation. In this study, we set forth to determine the role of GPNMB in systemic sclerosis (SSc) fibroblasts. Dermal fibroblasts were isolated from skin biopsies from healthy subjects and patients with diffuse cutaneous (dc)SSc. GPNMB was upregulated in dcSSc fibroblasts compared to normal fibroblasts, and correlated negatively with the modified Rodnan skin score. In addition, dcSSc fibroblasts secreted higher levels of soluble (s)GPNMB (147.4 ± 50.2 pg/ml vs. 84.8 ± 14.8 pg/ml, p<0.05), partly due to increased ADAM10. sGPNMB downregulated profibrotic genes in dcSSc fibroblasts and inhibited cell proliferation and gel contraction. The anti-fibrotic effect of sGPNMB was at least in part mediated through CD44, which is regulated by histone acetylation. TGFβ downregulated GPNMB and decreased the release of its soluble form in normal fibroblasts. In dcSSc fibroblasts, GPNMB is upregulated by its own soluble form. Our data demonstrate an anti-fibrotic role of sGPNMB in SSc and established a role for the ADAM10-sGPNMB-CD44 axis in dermal fibroblasts. Upregulating GPNMB expression might provide a novel therapeutic approach in SSc.
糖蛋白非转移性黑色素瘤蛋白 B（GPNMB）参与多种细胞功能，如细胞黏附、迁移、增殖和分化。在这项研究中，我们旨在确定 GPNMB 在系统性硬皮病（SSc）成纤维细胞中的作用。真皮成纤维细胞从健康受试者和弥漫性皮肤 SSc（dcSSc）患者的皮肤活检中分离出来。与正常成纤维细胞相比，dcSSc 成纤维细胞中 GPNMB 上调，与改良 Rodnan 皮肤评分呈负相关。此外，dcSSc 成纤维细胞分泌更高水平的可溶性（s）GPNMB（147.4±50.2 pg/ml 比 84.8±14.8 pg/ml，p<0.05），部分原因是 ADAM10 增加。sGPNMB 下调 dcSSc 成纤维细胞中的致纤维基因，并抑制细胞增殖和凝胶收缩。sGPNMB 的抗纤维化作用至少部分是通过 CD44 介导的，CD44 受组蛋白乙酰化调节。TGFβ下调 GPNMB 并减少其在正常成纤维细胞中的可溶性形式的释放。在 dcSSc 成纤维细胞中，GPNMB 自身的可溶性形式上调。我们的数据表明 sGPNMB 在 SSc 中具有抗纤维化作用，并确立了 ADAM10-sGPNMB-CD44 轴在真皮成纤维细胞中的作用。上调 GPNMB 的表达可能为 SSc 提供一种新的治疗方法。
Zotero 插件
