1. IGF-II regulates lysyl oxidase propeptide and mediates its effects in part via basic helix-loop-helix E40.
- Author
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Adewale AT, Sharma S, Mouawad JE, Nguyen XX, Bradshaw AD, and Feghali-Bostwick C
- Subjects
- Animals, Mice, Humans, Scleroderma, Systemic pathology, Scleroderma, Systemic metabolism, Scleroderma, Systemic genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Extracellular Matrix metabolism, Lung metabolism, Lung pathology, Bleomycin pharmacology, Disease Models, Animal, Female, Male, Protein-Lysine 6-Oxidase metabolism, Protein-Lysine 6-Oxidase genetics, Insulin-Like Growth Factor II metabolism, Insulin-Like Growth Factor II genetics, Pulmonary Fibrosis metabolism, Pulmonary Fibrosis pathology, Pulmonary Fibrosis genetics, Bone Morphogenetic Protein 1 metabolism, Bone Morphogenetic Protein 1 genetics
- Abstract
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., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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