Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.
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 > or =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.
Morikawa
Akira
A
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.
Ohara
Noriyuki
N
Xu
Qin
Q
Nakabayashi
Koji
K
DeManno
Deborah A
DA
Chwalisz
Kristof
K
Yoshida
Shigeki
S
Maruo
Takeshi
T
D000328:Adult; D051926:Basigin / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis* / Q000187:drug effects; D015536:Down-Regulation; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D066298:In Vitro Techniques; D007889:Leiomyoma / Q000188:drug therapy / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D009215:Myometrium / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000187:drug effects*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism
D004963:Estrenes; D010091:Oximes; D011980:Receptors, Progesterone; D019714:Tissue Inhibitor of Metalloproteinases; D051926:Basigin; C488516:asoprisnil; D003094:Collagen; D020782:Matrix Metalloproteinases