Inhibition of Hyaluronic Acid Synthesis Decreases Endometrial Cell Attachment, Migration, and Invasion


To characterize the effects of 4-methylumbelliferone (4-MU) on expression of the hyaluronic acid (HA) system and on attachment, migration, and invasion of endometrial epithelial (EECs) and stroma cells (ESCs) to peritoneal mesothelial cells (PMCs), this in vitro study was performed in an Academic Center. De-identified endometrial tissue samples used were from reproductive-aged women. EECs and ESCs isolated from menstrual endometrial biopsies were treated with 4-MU or vehicle. Real-time polymerase chain reaction and western blot were used to assess expression of HA synthases (HAS), hyaluronidase, and standard CD44. Established in vitro assays were used to assess attachment, migration, and invasion with and without treatment with 4-MU. Chi square and Student’s t-test were used to analyze the results as appropriate. The addition of 4-MU decreased mRNA and protein expression of HAS 2, HAS 3, and CD44 in EECs and ESCs compared to control. Treatment with 4-MU also decreased attachment, migration, and invasion of EECs and ESCs to PMCs compared to control. 4-MU decreases endometrial cell adhesion, migration, and invasion to PMCs. This effect appears to be mediated by a decrease in HAS 2, HAS 3, and CD44. 4-MU is a potential treatment for endometriosis. Future in vivo studies are needed to evaluate 4-MU as a therapeutic agent for endometriosis.

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The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2 TR001118 (JFK). The project described was supported by the Eunice Kennedy Shriver National Institute for Children Health and Development, National Institutes of Health, through Grant K23 HD097307 (JFK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The project was also supported by the American Society for Reproductive Medicine grant (JFK).

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Correspondence to Jennifer F. Knudtson.

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The authors declare that they have no conflict of interest.

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4-Methylumbelliferone (4-MU) inhibits hyaluronic acid synthesis and its receptor. The addition of 4-MU to endometrial cells decreases endometrial cell attachment, migration, and invasion to peritoneal mesothelial cells.

The material contained in the manuscript has not been published, has not been submitted, or is not being submitted elsewhere for publication. All authors are in agreement to submission of this manuscript.


This work was presented on October 10, 2018 at the American Society of Reproductive Medicine annual meeting in Denver, Colorado.

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McLaughlin, J.E., Santos, M.T., Binkley, P.A. et al. Inhibition of Hyaluronic Acid Synthesis Decreases Endometrial Cell Attachment, Migration, and Invasion. Reprod. Sci. 27, 1058–1063 (2020).

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  • Hyaluronic acid
  • 4-Methylumbelliferone
  • Endometriosis