Effect of Bone Morphogenetic Protein-7 on Folliculogenesis and Ovulation in the Rat1

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.

Activation of dormant ovarian follicles to generate mature eggs

“…Using in vitro cultures, mutant animals, specific inhibitors, and passive immuno-neutralization tests, several ovarian paracrine factors have been found to be important for the activation of cultured murine primordial follicles (5), including kit ligand (16), PDGF (17), neurotrophins (18), leukemia inhibitory factor (19), vascular endothelial growth factor (20), bone morphogenetic proteins (21), and FGF proteins (22,23). Although the exact factors involved in the activation of few primordial follicles to initiate growth under physiological states are still unknown, it is possible that key tyrosine kinase receptors respond to their ligands in oocytes by direct binding and activation of downstream PI3K and Akt enzymes.…”

Regulatory role of BMP2 and BMP7 in spermatogonia and Sertoli cell proliferation in the immature mouse

“…It is interesting to note that both BMP7 and activin are also involved in the paracrine control of ovarian function, and in particular granulosa cell function, including a stimulatory effect upon mitotic activity (42,43).…”

Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

“…Bambi is an inhibitor of BMPs (Loveland et al 2003), and BMP4 and BMP7 have been implicated in regulating primordial to primary follicle transition (Shimasaki et al 1999, Lee et al 2001, Nilsson & Skinner 2003. Agpt2 is a negative regulator of Agpt1 (Lindell et al 2001), and angiogenesis is important for follicular development.…”

“…Growth factors produced by the theca/interstitial cells that surround follicles and promote the primordial to primary follicle transition include bone morphogenic protein 4 (BMP4), BMP7 (Shimasaki et al 1999, Lee et al 2001, Nilsson & Skinner 2003, and keratinocyte growth factor (KGF or FGF7; Kezele et al 2005a). KGF is produced by isolated precursor theca cells surrounding primordial and early stage developing follicles (Kezele et al 2005a).…”