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

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...

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Autores principales: Yoshino, Osamu, Ono, Yosuke, Honda, Masako, Hattori, Kyoko, Sato, Erina, Hiraoka, Takehiro, Ito, Masami, Kobayashi, Mutsumi, Arai, Kenta, Katayama, Hidekazu, Tsuchida, Hiroyoshi, Yamada-Nomoto, Kaori, Iwahata, Shunsuke, Fukushi, Yoshiyuki, Wada, Shinichiro, Iwase, Haruko, Koga, Kaori, Osuga, Yutaka, Iwaoka, Michio, Unno, Nobuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693148/
https://www.ncbi.nlm.nih.gov/pubmed/33142814
http://dx.doi.org/10.3390/biomedicines8110467
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author Yoshino, Osamu
Ono, Yosuke
Honda, Masako
Hattori, Kyoko
Sato, Erina
Hiraoka, Takehiro
Ito, Masami
Kobayashi, Mutsumi
Arai, Kenta
Katayama, Hidekazu
Tsuchida, Hiroyoshi
Yamada-Nomoto, Kaori
Iwahata, Shunsuke
Fukushi, Yoshiyuki
Wada, Shinichiro
Iwase, Haruko
Koga, Kaori
Osuga, Yutaka
Iwaoka, Michio
Unno, Nobuya
author_facet Yoshino, Osamu
Ono, Yosuke
Honda, Masako
Hattori, Kyoko
Sato, Erina
Hiraoka, Takehiro
Ito, Masami
Kobayashi, Mutsumi
Arai, Kenta
Katayama, Hidekazu
Tsuchida, Hiroyoshi
Yamada-Nomoto, Kaori
Iwahata, Shunsuke
Fukushi, Yoshiyuki
Wada, Shinichiro
Iwase, Haruko
Koga, Kaori
Osuga, Yutaka
Iwaoka, Michio
Unno, Nobuya
author_sort Yoshino, Osamu
collection PubMed
description 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.
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spelling pubmed-76931482020-11-28 Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation Yoshino, Osamu Ono, Yosuke Honda, Masako Hattori, Kyoko Sato, Erina Hiraoka, Takehiro Ito, Masami Kobayashi, Mutsumi Arai, Kenta Katayama, Hidekazu Tsuchida, Hiroyoshi Yamada-Nomoto, Kaori Iwahata, Shunsuke Fukushi, Yoshiyuki Wada, Shinichiro Iwase, Haruko Koga, Kaori Osuga, Yutaka Iwaoka, Michio Unno, Nobuya Biomedicines Article 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. MDPI 2020-10-31 /pmc/articles/PMC7693148/ /pubmed/33142814 http://dx.doi.org/10.3390/biomedicines8110467 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yoshino, Osamu
Ono, Yosuke
Honda, Masako
Hattori, Kyoko
Sato, Erina
Hiraoka, Takehiro
Ito, Masami
Kobayashi, Mutsumi
Arai, Kenta
Katayama, Hidekazu
Tsuchida, Hiroyoshi
Yamada-Nomoto, Kaori
Iwahata, Shunsuke
Fukushi, Yoshiyuki
Wada, Shinichiro
Iwase, Haruko
Koga, Kaori
Osuga, Yutaka
Iwaoka, Michio
Unno, Nobuya
Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation
title Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation
title_full Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation
title_fullStr Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation
title_full_unstemmed Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation
title_short Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation
title_sort relaxin-2 may suppress endometriosis by reducing fibrosis, scar formation, and inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693148/
https://www.ncbi.nlm.nih.gov/pubmed/33142814
http://dx.doi.org/10.3390/biomedicines8110467
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