| Summary: | Ovulation is a complex and finely-tuned process whereby a series of closely-regulated events happen, including cumulus-oocyte complex (COC) expansion, resumption of oocyte meiosis and follicle rupture. These events must occur before luteinization; otherwise the oocytes are trapped within follicles and destined to degenerate. Appropriate timing requires specific changes in granulosa cell functions that are governed by gonadotropins and regulated by intrafollicular molecular regulators. In animal models, bone morphogenetic proteins (BMPs) are essential for successful ovulation by inhibiting early luteinization. However, the detailed functions and underlying mechanisms of BMPs on the ovulation/luteinization process have not been fully established. In the present research, immortalized (SVOG) and primary human granulosa cells were used to investigate the effects of recombinant human BMPs on steroid hormones and COC expansion-related protein production. Receptor-mediated signaling was investigated using activin receptor-like kinase (ALK) inhibitors and small interfering RNAs targeting ALKs and SMADs. In human granulosa cells, BMP4 and BMP7 suppress progesterone production and steroidogenic acute regulatory protein (StAR) expression while increasing estradiol production and aromatase expression. This fact suggests that BMPs could inhibit premature luteinization by decreasing the progesterone/estradiol ratio. BMPs (BMP4, BMP6, BMP7 and BMP15) up-regulate hyaluronan synthases 2 (HAS2) expressions and hyaluronan production as well as the expression of the hyaluronan binding protein versican. BMP4 also induced A Disintegrin and Metalloproteinase with TromboSPondin Repeats-1 (ADAMTS-1) protein levels and activity of versican proteolytic cleavage. It suggests that BMPs could promote COC mass formation while simultaneously loosing the matrix by increasing versican cleavage. In addition, the findings that the effects of BMPs on different gene expressions are differentially mediated by ALK inhibitors suggest that human granulosa cells have the capacity to signal via multiple BMP type I receptors in response to these factors, but that the receptor(s) are differentially coupled to specific target genes or cellular responses. Moreover, BMPs regulate different biological processes by activating different SMAD signaling: down-regulate progesterone production through canonical SMAD1/5/8 signaling, while up-regulate hyaluronan production through noncanonical SMAD2/3 signaling. These findings deepen knowledge of the physiological roles of BMPs during periovulatory interval and may lead to applying to in vitro fertilization (IVF) protocol improvement. === Medicine, Faculty of === Obstetrics and Gynaecology, Department of === Graduate
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