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UBC Theses and Dissertations

The roles of oocyte- and theca cell-derived bone morphogenetic proteins in human granulosa cells Chang, Hsun-Ming


Exerting a broad range of biological effects in various tissues, bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β superfamily. Accumulating evidence indicates that ovarian BMPs are critical regulators of ovarian function and play important roles in the female reproductive system. Mutual communication between oocytes and the surrounding somatic cells is mandatory for normal follicle development, as these locally expressed growth factors function mainly as paracrine/autocrine effectors in granulosa cells. Previous studies have shown that oocytes may secrete an anti-luteinization factor and theca cells may have luteinization-inhibiting activities. We therefore hypothesized that during the late follicular stage, oocyte-derived and theca cell-derived BMPs may prevent premature luteinization by down-regulating several ovulation-related genes. This study aims to investigate the anti-luteinization effects of oocyte- and theca cell-derived BMPs in human granulosa cells. An established immortalized human granulosa cell line (SVOG), granulosa cell tumor cell line (KGN) and primary granulosa-lutein cells were used as study models. Several parameters of luteinization were investigated following exposure to recombinant human BMP4, BMP7 or BMP15. Dual pharmacological and siRNA-based approaches were used to examine the underlying mechanisms and verify the specificity of the effects. Our studies demonstrate that oocyte-derived BMP15 functions as a paracrine factor to decrease progesterone production and that theca cell-derived BMP4 and BMP7 down-regulate PTX3 expression in human granulosa cells. In addition, all three growth factors decrease intercellular communication by down-regulating Cx43-coupled gap junction formation. Furthermore, both BMP4 and BMP7 increase the production of a luteinization inhibitor activin A by up-regulating the expression of inhibin βA subunit and furin. Interestingly, different BMPs act through differential subsets of type I receptor-driven SMAD-dependent pathways. These results suggest that oocytes and theca cells may play important roles in the prevention of premature luteinization, a process that is essential for normal ovarian function and fertility. Our findings provide important insight into ovarian biology, and may lead to the development of novel therapeutic tools for fertility regulation.

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