Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Public Health Sciences, Biostatistics and Bioinformatics, Medical University of South Carolina, Charleston, SC 29425, USA.
Int J Mol Sci. 2023 Jul 8;24(14):11234. doi: 10.3390/ijms241411234.
Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGFβ. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules ( ≤ 0.01) and ( ≤ 0.05), collagen type III ( ≤ 0.01), and the collagen posttranslational modification enzymes ( ≤ 0.05), ( ≤ 0.05), ( 0.065), ( ≤ 0.05), ( ≤ 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGFβ2 ( ≤ 0.01), as well as COL3A1, P4HA2, P4Hβ, and LOXL4 ( 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, , and and protein levels of CTSK ( ≤ 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA ( ≤ 0.05) and protein ( ≤ 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts ( 0.05) via the IGF1R/IR hybrid receptor, and SOX9 regulates TGFβ2 ( ≤ 0.05), TGFβ3 ( ≤ 0.05), COL3A1 ( ≤ 0.01), and P4HA2 ( ≤ 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis.
特发性肺纤维化（PF）与系统性硬化症（SSc）相关，导致发病率和死亡率显著增加。我们之前报道过，胰岛素样生长因子-II（IGF-II）在 SSc 患者的肺组织和成纤维细胞中过度表达，IGF-II 通过上调胶原 I、纤维连接蛋白和 TGFβ 促进纤维化。我们现在表明，IGF-II 增加了促纤维化信号分子（ ≤ 0.01）和（ ≤ 0.05）、III 型胶原（ ≤ 0.01）以及胶原翻译后修饰酶（ ≤ 0.05）、（ ≤ 0.05）、（0.065）、（ ≤ 0.05）、（ ≤ 0.05）的 mRNA 水平。IGF-II 增加了 TGFβ2（ ≤ 0.01）、COL3A1、P4HA2、P4Hβ 和 LOXL4 的蛋白水平（0.05）。相反，IGF-II 降低了胶原蛋白降解酶组织蛋白酶 K（CTSK）、、和的 mRNA 水平以及 CTSK 的蛋白水平（ ≤ 0.05）。与健康对照组相比，SOX9 在 SSc 肺组织中的 mRNA（ ≤ 0.05）和蛋白（ ≤ 0.01）水平过度表达。IGF-II 通过 IGF1R/IR 杂合受体诱导肺成纤维细胞中 SOX9 的表达（0.05），SOX9 调节 TGFβ2（ ≤ 0.05）、TGFβ3（ ≤ 0.05）、COL3A1（ ≤ 0.01）和 P4HA2（ ≤ 0.001）下游的 IGF-II。我们的结果确定了一个新的 IGF-II 信号轴和下游靶标，它们以 SOX9 依赖和独立的方式受到调节。我们的发现为 IGF-II 在促进肺纤维化中的作用提供了新的见解。
