Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation

Abstract

Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder; however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a comprehensive study on the effect of RLX-2 on endometriosis. We checked the expressions of LGR-7, a primary receptor of RLX-2, in endometriomas using immunohistochemistry. Endometriotic stromal cells (ESCs) purified from surgical specimens were used in in vitro experiments. The effects of RLX-2 on ESCs were evaluated by quantitative-PCR, ELISA, and Western blotting. Gel contraction assay was used to assess the contraction suppressive effect of RLX-2. The effect of RLX-2 was also examined in the endometriosis mouse model. LGR-7 was expressed in endometriotic lesions. In ESCs, RLX-2 increased the production of cAMP and suppressed the secretion of interleukin-8, an inflammatory cytokine, by 15% and mRNA expression of fibrosis-related molecules, plasminogen activator inhibitor-1 (PAI-1), and collagen-I by approximately 50% (p < 0.05). In the gel contraction assay, RLX-2 significantly suppressed the contraction of ESCs, which was cancelled by removing RLX-2 from the medium or by adding H89, a Protein Kinase A (PKA) inhibitor. In ESCs stimulated with RLX-2, p38 MAPK phosphorylation was significantly suppressed. In the endometriosis mouse model, administration of RLX-2 significantly decreased the area of the endometriotic-like lesion with decreasing fibrotic component compared to non-treated control (p = 0.01). RLX-2 may contribute to the control of endometriotic lesion by suppressing fibrosis, scar formation, and inflammation.

Interference of Known or Suspected Endometriosis in Reporting FDG PET/CT Performed in Another Indication

“…This inconstant 18 F-FDG uptake by lesions makes 18 F-FDG PET/CT not suited for routine localization of lesions of endometriosis. 3,4 In our series of patients referred to 18 F-FDG PET/CT for another indication but with past or recent diagnosis or suspected endometriosis, the patient-based detection rate of endometriosis with 18 F-FDG was 8 of 13 (62%), nonsignificantly greater than 32 of 73 (44%) obtained by pooling the results of 5 previous studies (Fisher exact test, P = 0.4). [8][9][10]13,18 It should be noted that the detection rate was highly variable between those series, from none of 9 (0%) 9 to 18 of 22 (82%) 8 in case of ovarian masses.…”

“…The main aims for this proposed change are to foster the evaluation of fibrosis in studies on endometriosis pathogenesis, to limit potential false negative diagnoses if pathologists stick stringently to the current definition of endometriosis requiring the demonstration of endometrial stromal and glands, and to consider fibrosis as a potential target for treatment in endometriosis. 4 Endometriosis is a common gynecologic condition occurring in 5% to 10% of women of reproductive age 5 and may also be present in 2% to 5% of postmenopausal women. 6,7 Regardless of predominant pathophysiology of endometriosis, both inflammation and active fibrosis may lead to increased glucose metabolism, which is detected on functional PET imaging with 18 F-FDG.…”

Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

“…Uterine tissue engrafted varied from one large (5 mm) piece (Peyneau et al, 2019) to up to six (2 mm) tissue punches (Kumar et al, 2014). Tissue was sutured or adhered to the peritoneum (Wilkosz et al, 2011;Mattos et al, 2019;Tal et al, 2019;Chang et al, 2020;Hattori et al, 2020;Li et al, 2020;Symons et al, 2020;Yoshino et al, 2020;Chen et al, 2021;Santorelli et al, 2021), intestinal mesentery (Mishra et al, 2020), abdominal wall (Peyneau et al, 2019), bowel mesentery (Ricci et al, 2011), and ovaries (Hayashi et al, 2020). Lesions sutured or adhered in the peritoneal cavity display characteristics similar to human lesions.…”

“…Other vehicles used in the delivery of drugs and agents in murine models include PBS (Bacci et al, 2009;Altan et al, 2010;Sanchez et al, 2017;Symons et al, 2020), water (Pittaluga et al, 2010;Horne et al, 2019), saline (Chen et al, 2009;Bilotas et al, 2010;Ricci et al, 2011;Dodds et al, 2017;Forster et al, 2019), polyethylene glycol (Santorelli et al, 2021), 0.1% bovine serum albumin/PBS (Yoshino et al, 2020), ethanol/PBS (Kumar et al, 2014), captisol (Kim et al, 2014), and IgG isotype (Silveira et al, 2013).…”

Emerging Roles for LGR4 in Organ Development, Energy Metabolism and Carcinogenesis

“…Group B contains LGR4, LGR5, and LGR6, which exhibit a high degree of homology and function as receptors for the Wnt-activating R-spondins ( Dubey et al, 2020 ). Group C is consisted of LGR7 and LGR8, which recognize relaxin ( Yoshino et al, 2020 ) and insulin-like peptide 3 (INSL3) ( Yeom et al, 2021 ), respectively.…”