Expression of Polyamine Oxidase in Fibroblasts Induces MMP-1 and Decreases the Integrity of Extracellular Matrix

Abstract

Polyamine oxidase (PAOX) (N1-acetylpolyamine oxidase) is a major enzyme in the polyamine catabolism pathway that generates hydrogen peroxide. Hydrogen peroxide plays a crucial role in skin aging via extracellular matrix (ECM) degradation by increasing the matrix metalloproteinase-1 (MMP-1) levels. We analyzed the integrity of the ECM in foreskin fibroblasts using PAOX expression. PAOX increased the MMP-1 secretion and type Ι collagen degradation in 2D and 3D cultures of fibroblasts, respectively. Similarly, PAOX overexpression increased the messenger ribonucleic acid (mRNA) level of MMP-1. PAOX expression induced polyamine catabolism, decreased the spermine levels, and increased the putrescine levels. However, the exogenous polyamine treatment did not change the MMP-1 and type I collagen levels as much as PAOX expression. PAOX expression increased the reactive oxygen species (ROS) production in fibroblasts, and exogenous hydrogen peroxide increased both the ROS production and MMP-1 secretion. Furthermore, N-acetylcysteine, an antioxidant, reversed the PAOX-induced ROS production and MMP-1 secretion. PAOX induced the signaling pathways that activate activator protein-1 (AP-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which are important transcription factors for MMP-1 transactivation. We concluded that PAOX increased the ROS levels in fibroblasts, leading to an increase in MMP-1 expression. Therefore, we propose that PAOX is a potential target molecule in protecting the ECM integrity.