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Hum. Reprod. Advance Access originally published online on February 15, 2008
Human Reproduction 2008 23(4):944-951; doi:10.1093/humrep/den025
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer

Akira Morikawa1, Noriyuki Ohara1, Qin Xu1, Koji Nakabayashi1, Deborah A. DeManno2, Kristof Chwalisz2, Shigeki Yoshida1 and Takeshi Maruo1,3

1 Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, 650-0017 Kobe, Japan 2 TAP Pharmaceutical Products Inc., Lake Forest, IL, USA

3Correspondence address. Tel: +81-78-382-6000; Fax: +81-78-382-6019; E-mail: maruo{at}kobe-u.ac.jp

BACKGROUND: A recent clinical trial demonstrated that selective progesterone receptor modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells.

METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis.

RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN (P < 0.05), MMP-1 (P < 0.05) and membrane type 1-MMP (MT1-MMP) (P < 0.01) protein contents, but significantly higher TIMP-1 (P < 0.05), TIMP-2 (P < 0.01), type I (P < 0.05) and type III (P < 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations ≥10–7 M for 48 h significantly (P < 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 (P < 0.05), TIMP-2 (P < 0.01), type I (P < 0.01) and type III (P < 0.05 at 10–7 M; P < 0.01 at 10–6 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells.

CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.

Key words: asoprisnil/extracellular matrix/extracellular matrix metalloproteinase inducer/leiomyoma/selective progesterone receptor modulator

Submitted on August 13, 2007; resubmitted on December 5, 2007; accepted on January 17, 2008.


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