Plasma High Mobility Group Box 1 (HMGB1), Osteopontin (OPN), and Hyaluronic Acid (HA) as Admissible Biomarkers for Endometriosis

Abstract

Identification of biomarkers for endometriosis is an unmet medical need that demands to be fulfilled. In this study, we first used a mouse model of endometriosis and evaluated the potential utility of select biomarkers based on serial observations. Since fibrosis is the end result of lesional development, we chose high mobility group box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA), all three of them have been well documented to be involved in endometriosis and fibrosis, as potential biomarkers. In addition, we performed immunohistochemistry analysis of HMGB1, OPN, and the receptors for HMGB1, such as toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), proliferating cell nuclear antigen (PCNA), interleukin-33 (IL-33), and receptor for advanced glycation endproducts (RAGE)–a pattern recognition receptor, with HMGB1 being its important ligand. We then evaluated the same set of putative markers in 30 women with ovarian endometriomas and 20 without endometriosis, and reevaluated the 3 plasma markers 3 months after the surgical removal of all visible endometriotic lesions. In mouse, the lesional staining levels of OPN, RAGE, and IL-33 were all significantly higher than that of normal endometrium, and increased progressively as lesions progressed. In contrast to HMGB1, TLR4, p-p65 and PCNA staining levels were decreased progressively. In humans, lesional staining levels of OPN correlated positively, while that of HMGB1 correlated negatively with the extent of fibrosis. All three plasma markers correlated positively with the extent of lesional fibrosis. Through this integrated approach, we identified plasma HMGB1, OPN and HA as promising admissible biomarkers for endometriosis.