Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells.
ABSTRACT To examine the effect of bone morphogenetic protein 7 (BMP-7) on FSH receptor (FSHR) expression in human granulosa cells.
Laboratory study using human samples.
Human granulosa cells were obtained from 60 women undergoing oocyte retrieval for IVF.
Human granulosa cells (GCs) were cultured with recombinant BMP-7, followed by RNA extraction.
mRNA levels of GCs were measured by real-time reverse-transcription polymerase chain reaction.
Bone morphogenetic protein 7 increased FSHR gene expression in human luteinized granulosa cells, whereas it decreased LH receptor gene expression. Bone morphogenetic protein 7 also increased FSH-induced cyclic adenosine monophosphate production in GCs, indicating up-regulation of the cellular response to FSH. Although BMP-7 increased gene expression of activin-betaA and -betaB in GCs, inhibition of activin function did not affect the BMP-7-induced FSHR gene expression.
These findings provide new insight into the biologic function of BMP-7 in the human ovary and demonstrate its unique mechanism of regulating FSHR action.
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ABSTRACT: Using molecular, cellular, and genetic approaches, recent studies examining the role of the bone morphogenetic protein (BMP) family of growth factors in the reproductive system have led to significant breakthroughs in our understanding of mammalian reproduction and fertility. Gene expression studies have revealed that key components of the BMP system (ligands, receptors, signaling molecules, and binding proteins) exhibit coordinated spatial and temporal expression patterns in fundamental cell types throughout the reproductive system. Availability of recombinant BMPs has enabled functional studies that have demonstrated important biological activities of BMPs in controlling cellular proliferation, differentiation, and apoptosis in reproductive tissues. The physiological importance of the BMP system for mammalian reproduction has been further highlighted by the elucidation of the aberrant reproductive phenotypes of animals with naturally occurring mutations or targeted deletions of certain BMP family genes. Collectively, these studies have established the concept that the BMP system plays a crucial role in fertility in female and male mammals. The purpose of this article is to review the evidence underpinning the importance of the BMP system in mammalian reproduction.Endocrine Reviews 03/2004; 25(1):72-101. · 14.87 Impact Factor
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ABSTRACT: We have previously established the presence of a functional bone morphogenetic protein (BMP) system in the ovary by demonstrating the expression of BMP ligands and receptors as well as novel cellular functions. Specifically, BMP-4 and BMP-7 are expressed in theca cells, and their receptors by granulosa cells. These BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. To investigate the underlying mechanism of the differential regulation, we analyzed mRNA levels for key regulators in the steroid biosynthetic pathways by RNase protection assay. BMP-7 enhanced P450 aromatase (P450(arom)) but suppressed steroidogenic acute regulatory protein (StAR) mRNAs induced by FSH, whereas mRNAs encoding further-downstream steroidogenic enzymes, including P450 side-chain cleavage enzyme and 3beta-hydroxysteroid dehydrogenase, were not significantly altered. These findings suggest that BMP-7 stimulation and inhibition of P450(arom) and StAR mRNA expression, respectively, may play a role in the mechanisms underlying the differential regulation of estradiol and progesterone production. To establish the physiological relevance of BMP functions, we investigated the in vivo effects of injections of recombinant BMP-7 into the ovarian bursa of rats. Ovaries treated with BMP-7 had decreased numbers of primordial follicles, yet had increased numbers of primary, preantral, and antral follicles, suggesting that BMP-7 may act to facilitate the transition of follicles from the primordial stage to the pool of primary, preantral, and antral follicles. In this regard, we have also found that BMP-7 caused an increase in DNA synthesis and proliferation of granulosa cells from small antral follicles in vitro. In contrast to the stimulatory activity, BMP-7 exhibited pronounced inhibitory effects on ovulation rate and serum progesterone levels. These findings establish important new biological activities of BMP-7 in the context of ovarian physiology, including folliculogenesis and ovulation.Biology of Reproduction 11/2001; 65(4):994-9. · 4.03 Impact Factor
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ABSTRACT: The aim of this study was to investigate the actions of both activin and FSH-suppressing protein (FSP)/follistatin either alone or in combination on FSH receptor number and on the responsiveness of granulosa cells to FSH and LH. Granulosa cells were harvested from diethylstilbestrol-treated immature Sprague-Dawley rats and cultured 48 h in serum-free medium with or without treatment. Activin treatment alone (3-100 ng/ml) resulted in a 4-fold increase in FSH receptor number with no change in binding affinity. This effect of activin was inhibited 31% by FSP (100 ng/ml) treatment which alone had no effect on FSH receptor number. Treatment with activin (100 ng/ml) prevented FSH-induced down-regulation of FSH receptor number, whereas at lower concentrations (3-30 ng/ml) activin enhanced down-regulation of FSH receptor number by 20% (P less than 0.05). In contrast, FSP alone prevented FSH-induced down-regulation by increasing FSH receptor number up to 40-50%. Pretreatment of granulosa cells with activin, but not FSP, for 24 h increased the responsiveness of cells to FSH (20 ng/ml) and LH (40 ng/ml) shown by increases in aromatase activity, progesterone, and immunoreactive inhibin production over and above control in a manner which depended upon activin doses. We conclude that 1) activin enhancement of FSH action on rat granulosa cells may be mediated in part via regulation of FSH receptor number, and 2) the effects of FSP on granulosa cells are likely to be due to its activin binding properties.Endocrinology 10/1992; 131(3):1009-16. · 4.72 Impact Factor