MPS disorders result from a deficiency or absence of glycosaminoglycan (GAG) degrading enzymes leading to an imbalance between the synthesis and degradation of GAGs and their subsequent accumulation in a range of cells. The inhibition of GAG synthesis using small chemical inhibitors has been proposed as a novel therapeutic approach to treatment and is a minimally invasive way to treat hard-to-treat tissues such as brain and bone. We have shown that 2 small chemical inhibitors, rhodamine B and a fluorinated analog of N-acetylglucosamine (F-GlcNAc) can positively affect somatic, brain and bone disease using mouse models of MPS that accumulate heparan sulphate.
The mechanisms of action of inhibitors of GAG synthesis are poorly understood and the efficacy of these inhibitors in MPS diseases that store chondroitin/dermatan (CS/DS) or keratan sulphate (KS) is currently unknown. In this study we evaluated rhodamine B and F-GlcNAc in bovine chondrocyte and cartilage chip explants in vitro to determine their effect on CS/DS and KS and on an intact extracellular matrix.
Both inhibitors decreased the amount and size of newly synthesised proteoglycans. GAG chain size (CS/DS and KS) were decreased in the presence of F-GlcNAc but not rhodamine B. The expression of genes responsible for the initiation and elongation of CS/DS and KS GAGs were downregulated in the presence of rhodamine B but not in the presence of F-GlcNAc. Thus the 2 chemical inhibitors appear to inhibit GAG synthesis via different modes of action.
The results show that these inhibitors can be used in models of MPS that store CS/DS or KS and are potential therapeutics for MPS patients. Since the 2 inhibitors have different modes of action, using them in combination will enhance their efficacy.