The role of hyaluronic acid and its receptors in the pathogenesis of endometriosis

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Abstract/Summary Endometriosis is a common gynecologic disease affecting ~10% of reproductive-age women, the third leading cause of gynecologic hospitalization, a leading cause of hysterectomy in reproductive-age women, and responsible for $22 billion in U.S. health care costs annually. The mechanisms that contribute actual attachment of endometrial cells (ECs) to peritoneal mesothelial cells (PMCs) and subsequent sub peritoneal invasion and formation endometriotic lesions remain elusive and understudied. Our published and ongoing studies discovered that; (1) ECs rapidly attach to PMCs and invade the basement membrane within a few hours of attachment; (2) Attachment of ECs from women with endometriosis to PMCs is greater than ECs from women without endometriosis; (3) Hyaluronan (Hyaluronic acid, HA) and CD44, a receptor for hyaluronan (aka hyaladherins, HAA) play an essential role in endometriosis. In preliminary studies, knocking out CD44 or RHAMM (both of which function as HA receptors) significantly reduced endometriosis lesion formation. A knowledge gap exits as to how HA and its receptors contribute to ECs attaching to PMCs leading to initiation, progression of endometriosis and this limits exploitation of HA/HAA axis for therapeutic use. Hymecromone (4- methylumbelliferone, 4-MU), a drug widely used in bile therapy in humans, has the ability to inhibit HA biosynthesis and its interactions with HAA. We reason that 4-MU's ability to decrease HA/HAA axis signaling can be exploited therapeutically to block the development and progression of endometrial lesions. The objective of this study is to examine how HA and HAA interactions play a role in early endometriotic lesion formation and progression, as well as to exploit the therapeutic potential of 4-MU. The central hypothesis is that HA receptors play an important role in the attachment, invasion of menstrual endometrial cells contributing to early endometriotic lesions and that 4-MU will block the development and progression of endometrial lesions by blocking HA synthesis. In Aim1, we will define how HA/HAA interaction affect signal transduction pathways that influence biological properties of the endometrial cells with or without their expression. In Aim2, we will establish the therapeutic efficacy of blocking HA/HAA axis with 4-MU in a non-human primate model and explants, organoids derived from human endometriotic lesions. This proposal is highly innovative due to the use of unique KO mice models (lacking both CD44 and RHAMM) and testing the therapeutic efficacy of 4-MU, using non-human primate model and human explants and organoids. Further, this study introduces a new paradigm of treating endometriosis patients using an FDA approved drug, 4-MU, and identifying therapeutic response biomarkers. Outcomes of these studies will provide mechanistic insight into the pathogenesis of endometriosis and will help to test the therapeutic efficacy of 4-MU to block the development and progression of endometriotic lesions. This will provide a secondary prevention approach to treat women who have had laparoscopic surgery to treat endometriosis.