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

Research output: Contribution to journalArticle

Abstract

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
Volume61
Issue number2
DOIs
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). https://doi.org/10.1167/iovs.61.2.27