A functional bone morphogenetic protein system in the ovary

A functional bone morphogenetic protein system in the ovary

^*Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093-0633; ^§Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan; and ^¶Creative BioMolecules Inc., Hopkinton, MA 01748

Edited by Anthony P. Mahowald, The University of Chicago, Chicago, IL, and approved May 3, 1999 (received for review March 19, 1999)

Abstract

Bone morphogenetic proteins (BMPs) comprise a large group of polypeptides in the transforming growth factor β superfamily with essential physiological functions in morphogenesis and organogenesis in both vertebrates and invertebrates. At present, the role of BMPs in the reproductive system of any species is poorly understood. Here, we have established the existence of a functional BMP system in the ovary, replete with ligand, receptor, and novel cellular functions. In situ hybridization histochemistry identified strong mRNA labeling for BMP-4 and -7 in the theca cells and BMP receptor types IA, IB, and II in the granulosa cells and oocytes of most follicles in ovaries of normal cycling rats. To explore the paracrine function of this BMP system, we examined the effects of recombinant BMP-4 and -7 on FSH (follicle-stimulating hormone)-induced rat granulosa cytodifferentiation in serum-free medium. Both BMP-4 and -7 regulated FSH action in positive and negative ways. Specifically, physiological concentrations of the BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. These effects were dose- and time-dependent. Furthermore, the BMPs increased granulosa cell sensitivity to FSH. Thus, BMPs have now been identified as molecules that differentially regulate FSH-dependent estradiol and progesterone production in a way that reflects steroidogenesis during the normal estrous cycle. As such, it can be hypothesized that BMPs might be the long-sought “luteinization inhibitor” in Graafian follicles during their growth and development.

Footnotes

↵ † To whom all correspondence should be addressed at: Department of Reproductive Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0633. e-mail: sshimasaki{at}ucsd.edu.
↵ ‡ Present address: Department of Applied Dental Medicine, Southern Illinois University School of Dental Medicine, 2800 College Avenue, Alton, IL 62002-4700.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

BMP,

bone morphogenetic protein;

BMPR,

BMP receptor;

E,

estradiol;

FSH,

follicle-stimulating hormone;

P,

progesterone;

TGF-β,

transforming growth factor β