Characteristics of Hyaluronan Synthesis Inhibition by 4-Methylumbelliferone in Orbital Fibroblasts

Erika Galgoczi, Florence Jeney, Monika Katko, Annamaria Erdei, Annamaria Gazdag, Livia Sira, Miklos Bodor, Eszter Berta, Bernadett Ujhelyi, Zita Steiber, Ferenc Gyory, Endre V. Nagy

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Purpose: Hyaluronan (HA) overproduction by orbital fibroblasts (OFs) is a major factor in the pathogenesis of Graves' orbitopathy (GO). 4-methylumbelliferone (4-MU) is an inhibitor of HA synthesis in different cell types in vitro and has beneficial effects in animal models of autoimmune diseases. Methods: HA production and mRNA expression of HA synthases (HAS1, HAS2, and HAS3) and hyaluronidases (HYAL1 and HYAL2) were measured in the presence and absence of 4-MU in unstimulated and transforming growth factor-β-stimulated fibroblasts from GO orbital (n = 4), non-GO orbital (n = 4), and dermal origin (n = 4). Results: The 4-MU treatment (1 mM) for 24 hours resulted in an average 87% reduction (P < 0.001) of HA synthesis, decreased the expression of the dominant HAS isoform (HAS2) by 80% (P < 0.0001), and increased the HYAL2 expression by 2.5-fold (P < 0.001) in control OFs, GO OFs, and dermal fibroblasts (DFs) regardless of the origin of the cells. The proliferation rate of all studied cell lines was reduced to an average 16% by 4-MU (P < 0.0001) without any effects on cell viability. HA production stimulated by transforming growth factor-β was decreased by 4-MU via inhibition of stimulated HAS1 expression in addition to the observed effects of 4-MU in unstimulated cases. Characteristics of HA synthesis inhibition by 4-MU did not differ in OFs compared with DFs. Conclusions: 4-MU has been found to inhibit the HA synthesis and the proliferation rate in OFs in vitro, adding it to the list of putative therapeutic agents in a disease the cure of which is largely unresolved.

Original languageEnglish
Number of pages1
JournalInvestigative ophthalmology & visual science
Issue number2
Publication statusPublished - Feb 7 2020

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Galgoczi, E., Jeney, F., Katko, M., Erdei, A., Gazdag, A., Sira, L., Bodor, M., Berta, E., Ujhelyi, B., Steiber, Z., Gyory, F., & Nagy, E. V. (2020). Characteristics of Hyaluronan Synthesis Inhibition by 4-Methylumbelliferone in Orbital Fibroblasts. Investigative ophthalmology & visual science, 61(2).