Substrate stiffness mediates osteogenic and adipogenic differentiation of osteosarcoma through the PIEZO1 / ITGB1 -YAP -EZH2 signaling pathway

Abstract

Abstract Most osteosarcoma (OS) are poorly differentiated histopathologically, when normal osteogenic differentiation is disrupted, growth factors stimulate uncontrolled proliferation of precursor cells, leading to osteosarcoma development. Differentiation therapy aims to slow disease progression by restoring the osteogenic differentiation process of OS cells and is considered a new approach to treating OS. However, there are currently too few studies on the mechanism of osteogenic and adipogenic differentiation of osteosarcoma, which puts the development of differentiation therapeutic drugs into a bottleneck. Previous studies have shown that matrix stiffness can regulate osteogenic and adipogenic differentiation in mesenchymal stem cells. In this study, we simulated different stiffnesses in vitro to investigate the mechanism of matrix stiffness affecting osteogenic and adipogenic differentiation of osteosarcoma. We demonstrate that PIEZO1 plays a critical regulatory role in sensing matrix stiffness in osteogenic and adipogenic differentiation of osteosarcoma. When OS are cultured on the stiff matrix, integrin beta 1 (ITGB1) increases and cooperates with PIEZO1 to promote YAP entering the nucleus. The YAP enters the nucleus to inhibit EZH2, thereby inhibiting the expression of H3K27me3 and increasing RUNX2 expression, and cells differentiate toward osteogenesis. Our results are new advances in research on differentiation treatment of osteosarcoma, can help understand the pathological changes in osteosarcoma, and are expected to become new targets for future drug design.