Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF. We sought to identify downstream regulatory mediators of IGF-II. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than control lung tissues. LOX-PP-mediated changes were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP, were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, BMP1, and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localized to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP, and restored features of ECM deregulation triggered by IGF-II. Our findings indicate that IGF-II, BHLHE40, and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression.

中文翻译：

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IGF-II 调节赖氨酰氧化酶前肽并部分通过碱性螺旋-环-螺旋 E40 介导其作用


肺纤维化（PF）是系统性硬化症（SSc）的一种临床严重且通常致命的并发症。我们的小组之前曾报道过胰岛素样生长因子 II (IGF-II) 和赖氨酰氧化酶 (LOX) 在 SSc-PF 中的促纤维化作用。我们试图确定 IGF-II 的下游调节介质。在目前的工作中，我们发现 SSc 肺组织的总（N-糖基化/非糖基化）LOX 前肽 (LOX-PP) 基线水平高于对照肺组织。 LOX-PP 介导的变化与 SSc-PF 进展中涉及的细胞外基质 (ECM) 失调一致。此外，Tolloid-like 1 (TLL1) 和骨形态发生蛋白 1 (BMP1)（可裂解 ProLOX 释放 LOX-PP 的酶）分别在 SSc 肺纤维化和博来霉素 (BLM) 诱导的小鼠肺纤维化模型中增加。此外，IGF-II 调节 ProLOX、活性 LOX、LOX-PP、BMP1 和 TLL1 亚型的水平。 E 类碱性螺旋-环-螺旋蛋白 40 (BHLHE40) 转录因子定位于细胞核，响应 IGF-II。 BHLHE40 沉默下调的 TLL1 同工型和 LOX-PP，并恢复 IGF-II 触发的 ECM 失调的特征。我们的研究结果表明，IGF-II、BHLHE40 和 LOX-PP 可以作为阻止 SSc-PF 进展的治疗干预目标。