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The Modulatory Role of Transforming Growth Factor ß1 and Androstenedione on Follicle-Stimulating Hormone-Induced Gelatinase Secretion and Steroidogenesis in Rat Granulosa Cells¹

Institute of Molecular and Cellular Biology,³ National Taiwan University, Taipei 106, Taiwan Institute of Physiology,⁴ National Yang-Ming University, Taipei 112, Taiwan Institute of Biological Chemistry,⁵ Academia Sinica, Taipei 115, Taiwan Department of Nursing,⁶ Kang-Ning College of Nursing, Taipei 114, Taiwan Department of Cell Biology and Biochemistry,⁷ Texas Tech University Health Sciences Center, Lubbock, Texas 79430

To investigate the potential roles of matrix metalloproteinases (MMPs) in ovarian granulosa cell differentiation, we studied the interactive effects of FSH and local ovarian factors, transforming growth factor ß1 (TGFß1) and androstenedione, on gelatinase secretion and progesterone production in rat ovarian granulosa cells. Granulosa cells of eCG-primed immature rats were treated once with various doses of FSH and TGFß1 and androstenedione alone or in combinations for 2 days. Conditioned media were analyzed for gelatinase activity using gelatin-zymography/densitometry and progesterone levels using enzyme immunoassay. Cell lysates were analyzed for steroidogenic acute regulatory (StAR) and cholesterol side-chain-cleavage (P450scc) enzyme protein levels. This study demonstrates for the first time that FSH dose-dependently increased the secretion of a major 63-kDa gelatinase and minor 92- and 67-kDa gelatinases. TGFß1 also dose-dependently increased the secretion of 63-kDa gelatinase, while androstenedione alone had no effect. The 92-kDa gelatinase was identified as the pro-MMP9 that could be cleaved by aminophenylmercuric acetate into the 83-kDa active form. Importantly, we show that TGFß1 and androgen act in an additive manner to enhance FSH stimulatory effects both on the secretion of gelatinases and the production of progesterone. We further show by immunoblotting that the enhancing effect of TGFß1 and androstenedione on FSH-stimulated steroidogenesis is partly mediated through the increased level of StAR protein and/or P450scc enzyme. In conclusion, this study indicates that, during antral follicle development, TGFß1 and androgen act to enhance FSH promotion of granulosa cell differentiation and that the process may involve the interplay of modulating cell- to-matrix/cell-to-cell interaction and steroidogenic activity.

¹ This work was supported by grants from National Science Council of Taiwan NSC 87-2314-B-010-102 and NSC 89-2320-B-010-058 (to J.-J.H.), Council of Agriculture of Taiwan 90-1.4.5-F1 (to F.-C.K.), NSC 87-2311- B-001-103 (to M.-T.L.), by awards from the Medical Research and Advancement Foundation in memory of Dr. Chi-Shuen Tsou, Taiwan (to J.- J.H.), and by grant HD17481 from the NIH and funds from the Robert A. Welch Foundation (to D.M.S.).

² Correspondence: Jiuan-Jiuan Hwang, Institute of Physiology, School of Medicine, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, Taiwan. FAX: 886 2 28264049; jiuanh{at}ym.edu.tw

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