title: Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase.
abstract: 4-Methylumbelliferone (4-MU) is described as a selective inhibitor of hyaluronan (HA) production. It is thought that 4-MU depletes UDP-glucuronic acid (UDP-GlcUA) substrate for HA synthesis and also suppresses HA-synthase expression. The possibility that 4-MU exerts at least some of its actions via regulation of UDP-glucose dehydrogenase (UGDH), a key enzyme required for both HA and sulphated-glycosaminoglycan (sGAG) production, remains unexplored. We therefore examined the effects of 4-MU on basal and retroviral UGDH-driven HA and sGAG release in cells derived from chick articular cartilage and its influence upon UGDH protein and mRNA expression and HA and sGAG production. We found that 4-MU: i) suppressed UGDH mRNA and protein expression and chondrogenic matrix accumulation in chick limb bud micromass culture, ii) significantly reduced both HA and sGAG production and iii) more selectively reversed the potentiating effects of UGDH overexpression on the production of HA than sGAG. Understanding how GAG synthesis is controlled and the mechanism of 4-MU action may inform its future clinical success.
authors.affiliation: Division of Diabetes and Nutritional Sciences, School of Medicine, Kings College London, University of London, United Kingdom.
authors.forename: C E
authors.initials: CE
authors.lastname: Clarkin
authors.forename: S
authors.initials: S
authors.lastname: Allen
authors.forename: C P
authors.initials: CP
authors.lastname: Wheeler-Jones
authors.forename: E R
authors.initials: ER
authors.lastname: Bastow
authors.forename: A A
authors.initials: AA
authors.lastname: Pitsillides
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D020219:Chondrogenesis / Q000187:drug effects*; D017077:Culture Media, Conditioned; D005109:Extracellular Matrix / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000494:pharmacology; D018878:Limb Buds / Q000166:cytology; D058990:Molecular Targeted Therapy; D014158:Transcription, Genetic; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D006025:Glycosaminoglycans; C013786:A73025; D006923:Hymecromone; D006820:Hyaluronic Acid; D014533:Uridine Diphosphate Glucose Dehydrogenase