Signaling at the Crossroads: Matrix-Derived Proteoglycan and Reactive Oxygen Species Signaling

Significance: Proteoglycans (PGs), besides their structural contribution, have emerged as dynamic components that mediate a multitude of cellular events. The various roles of PGs are attributed to their structure, spatial localization, and ability to act as ligands and receptors. Reactive oxygen species (ROS) are small mediators that are generated in physiological and pathological conditions. Besides their reactivity and ability to induce oxidative stress, a growing body of data suggests that ROS signaling is more relevant than direct radical damage in development of human pathologies. Recent Advances: Cell surface transmembrane PGs (syndecans, cluster of differentiation 44) represent receptors in diverse and complex transduction networks, which involve redox signaling with implications in cancer, fibrosis, renal dysfunction, or Alzheimer's disease. Through NADPH oxidase (NOX)-dependent ROS, the extracellular PG, hyaluronan is involved in osteoclastogenesis and cancer. The ROS sources, NOX1 and NOX4, increase biglycan-induced inflammation, while NOX2 is a negative regulator. Critical Issues: The complexity of the mechanisms that bring ROS into the light of PG biology might be the foundation of a new research area with significant promise for understanding health and disease. Important aspects need to be investigated in PG/ROS signaling: the discovery of specific targets of ROS, the precise ROS-induced chemical modifications of these targets, and the study of their pathological relevance. Future Directions: As we become more and more aware of the interactions between PG and ROS signaling underlying intracellular communication and cell fate decisions, it is quite conceivable that this field will allow to identify new therapeutic targets.