Chondroitin and dermatan sulfate exposure induces a wound healing state in fibroblasts through Cux1-mediated SerpinB2 transcriptional repression

ABSTRACT Mucopolysaccharidoses (MPS) are a group of syndromes characterized by the accumulation of sulfated glycosaminoglycans (sGAGs), leading to profound connective tissue alterations, including impaired endochondral ossification. The function of sGAGs involves determining the mechanical properties of the extracellular matrix and regulating growth factor signaling pathways, such as Fgf2. In this study, we investigated the deposition of chondroitin sulfate and dermatan sulfate, two major sGAGs, and their resemblance to wound healing states in human fibroblasts. Our findings indicate that this condition alters cell adhesion, providing a potential explanation for fibrosis-like changes observed in MPS patients. Furthermore, we elucidate the molecular pathway responsible for this effect, wherein increased Cathepsin L activation leads to the processing of the transcription factor Cux1 into a stable form capable of regulating the expression of target genes, including SERPINB2. The presence of similar changes in cell adhesion in human-induced pluripotent stem cell-derived mesenchymal cells further reinforces the significance of sGAGs in cell adhesion and sheds light on possible mechanisms underlying altered endochondral ossification in MPS patients.