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

Area of Science:

• Fibrosis research
• Molecular biology
• Systemic Sclerosis research

Background:

• Pulmonary fibrosis (PF) is a severe complication of Systemic Sclerosis (SSc).
• Previous work identified profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF.
• The downstream mediators of IGF-II in SSc-PF remain to be fully elucidated.

Purpose of the Study:

• To identify downstream regulatory mediators of IGF-II in the context of SSc-PF.
• To investigate the roles of LOX-Propeptide (LOX-PP), Tolloid-like 1 (TLL1), Bone Morphogenetic Protein 1 (BMP1), and BHLHE40 in SSc-PF.
• To explore potential therapeutic targets for SSc-PF.

Main Methods:

• Analysis of human SSc lung tissues and a bleomycin-induced murine lung fibrosis model.
• Measurement of LOX-PP, TLL1, and BMP1 levels.
• Investigation of IGF-II's regulatory effects on various proteins.
• Assessment of BHLHE40's role via gene silencing and its impact on downstream targets and extracellular matrix (ECM) deregulation.

Main Results:

• SSc lung tissues exhibit elevated LOX-PP levels compared to controls.
• TLL1 and BMP1 are increased in SSc lung fibrosis and the BLM model, respectively.
• IGF-II influences ProLOX, active LOX, LOX-PP, BMP1, and TLL1 isoforms.
• BHLHE40 activation by IGF-II leads to nuclear localization, and its silencing downregulates TLL1 and LOX-PP, restoring ECM homeostasis.

Conclusions:

• IGF-II, BHLHE40, and LOX-PP are key players in SSc-PF pathogenesis.
• The IGF-II/BHLHE40/LOX-PP axis contributes to ECM deregulation in SSc-PF.
• These factors represent promising therapeutic targets to potentially halt SSc-PF progression.