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Differential Expression, Regulation, and Induction of Smads, Transforming Growth Factor-ß Signal Transduction Pathway in Leiomyoma, and Myometrial Smooth Muscle Cells and Alteration by Gonadotropin-Releasing Hormone Analog

Department of Obstetrics/Gynecology, University of Florida, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Dr. Nasser Chegini, Department of Obstetrics/Gynecology, University of Florida, Box 100294, Gainesville, Florida 32610. E-mail: cheginin{at}obgyn.ufl.edu.

The objective of this study was to further elucidate the role of TGFß and GnRH analog (GnRHa) in leiomyoma growth and regression. We examined the expression of Smads, TGFß receptor intracellular signaling molecules, in leiomyoma and myometrial smooth muscle cells (LSMC and MSMC), and determined whether TGFß and GnRHa differentially regulate their expression and induction in these cells. Using semiquantitative RT-PCR, Western blot analysis, and immunohistochemistry, we demonstrated that leiomyoma, myometrium, LSMC, and MSMC express receptor-activated Smad3, common Smad4, and the inhibitory Smad7 mRNA and protein and showed that TGFß1, in a time-dependent manner, transiently induced Smad7 expression, with Smad3 and Smad4 remaining largely unchanged. TGFß1 increased the rate of Smad and phosphorylated Smad3 (pSmad3) induction in both cell types. Pretreatment with TGFß type II receptor antisense oligonucleotide resulted in a trend toward a lower TGFß-induced pSmad3. GnRHa, in a dose- and time-dependent manner, increased the expression of Smad7 mRNA and the rapid induction of Smad3, Smad4, and Smad7 as well as pSmad3, which declined to control values at doses above 1 µM in MSMC, but not in LSMC. GnRHa-induced pSamd3 was partly inhibited by a GnRH antagonist (antide). We concluded that leiomyoma, myometrium, LSMC, and MSMC express Smads, which are differentially expressed, induced, and activated by TGFß and are altered as a result of GnRHa treatment. These results suggest that TGFß and GnRHa mediate their actions through cross-talk involving Smads and most likely other signaling pathways that result in leiomyoma growth and regression.

This work was supported by NIH Grant HD-37432. This work was presented in part at the 48th Annual Meeting of the Society for Gynecological Investigation, Los Angeles, California, March 2002.

Abbreviations: ECM, Extracellular matrix; ERK, extracellular signal-regulated kinase; GnRHa, GnRH analog; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; LA, leuprolide acetate; LSMC, leiomyoma smooth muscle cell; MSMC, myometrial smooth muscle cell; PKC, protein kinase C; RSmad, regulatory Smad.

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