IGF-II regulates lysyl oxidase propeptide and mediates its effects in part via basic helix-loop-helix E40

• Published in: Matrix biology 2024-09, Vol.132, p.24-33
• Main Authors: Adewale, Adegboyega Timothy, Sharma, Shailza, Mouawad, Joe E., Nguyen, Xinh-Xinh, Bradshaw, Amy D., Feghali-Bostwick, Carol
• Format: Article
• Language: English
• Subjects: Bone Morphogenetic Protein 1; Class E Basic Helix-Loop-Helix protein 40; Insulin-like Growth Factor II; Lysyl Oxidase Propeptide; Systemic Sclerosis Pulmonary Fibrosis; Tolloid-Like 1
• ISSN: 0945-053X; 1569-1802; 1569-1802
• DOI: 10.1016/j.matbio.2024.06.002

•The mediators of extracellular matrix deregulation downstream of Insulin-like growth factor II (IGF-II) were investigated.•Levels of pro-Lysyl Oxidase (ProLOX), its cleavage products LOX, and Lysyl oxidase propeptide (LOX-PP) as well as the enzymes that cleave ProLOX, Tolloid-like 1 (TLL1) isoforms and bone morphogenetic protein 1 (BMP1), increased in response to IGF-II.•LOX-PP levels were increased in human systemic sclerosis lung tissues and experimental murine lung fibrosis, and LOX-PP increased levels of markers of fibrosis by primary pulmonary fibroblasts.•The class E basic helix-loop-helix protein 40 (BHLHE40) regulates IGF-II-induced LOX-PP and TLL1 isoforms, and its deficiency increases matrix metalloprotease (MMP) 1, and restores MMP3 and cathepsin K levels repressed in response to IGF-II.•Our findings suggest that LOX-PP and BHLHE40 are new potential therapeutic targets in SSc-associated pulmonary fibrosis. 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.