PROGESTERONE-DEPENDENT EXPRESSION OF KERATINOCYTE GROWTH-FACTOR MESSENGER-RNA IN STROMAL CELLS OF THE PRIMATE ENDOMETRIUM - KERATINOCYTE GROWTH-FACTOR AS A PROGESTOMEDIN

In vitro studies have shown that keratinocyte growth factor (KGF, also known as FGF-7) is secreted by fibroblasts and is mitogenic specifica lly for epithelial cells. Therefore, KGF may be an important paracrine mediator of epithelial cell proliferation in vivo. Because stromal ce lls are thought to influence glandular proliferation in the primate en dometrium, we investigated the hormonal regulation and cellular locali zation of KGF mRNA expression in the rhesus monkey uterus. Tissues wer e obtained both from naturally cycling monkeys in the follicular and l uteal phases of the cycle, and from spayed monkeys that were either un treated or treated with estradiol (E2) alone, E2 followed by progester one (P), E2 PIUS P, or E2 PIUS P plus an antiprogestin (RU 486). North ern blot analysis of total RNA with P-32-labeled probes revealed that the level of KGF mRNA in the endometrium was 70-100-fold greater in th e luteal phase or after P treatment than in untreated, E2-treated, or follicular phase animals. Northern analysis also showed that KGF mRNA was present in the myometrium but was unaffected by hormonal state. RU 486 treatment prevented the P-induced elevation of endometrial KGF mR NA. P-dependent elevation of endometrial KGF expression was confirmed by measurement of KGF protein in tissue extracts using a two-site enzy me-linked immunosorbent assay. In situ hybridization with nonradioacti ve digoxigenin-labeled cDNA probes revealed that the KGF mRNA signal, which was present only in stromal and smooth muscle cells, was-substan tially increased by P primarily in the stromal cells located in the ba salis region. Smooth muscle cells in the myometrium and the walls of t he spiral arteries also expressed KGF mRNA, but the degree of this exp ression did not differ with hormonal state. P treatment led to increas ed proliferation in the glandular epithelium of the basalis region and to extensive growth of the spiral arteries. We conclude that the P-de pendent increase in endometrial KGF resulted from a dual action of P: (a) a P-dependent induction of KGF expression in stromal cells, especi ally those in the basalis (zones Ill and IV), and (b) a P-dependent in crease in the number of KGF-positive vascular smooth muscle cells caus ed by the proliferation of the spiral arteries. KGF is one of the firs t examples in primates of a P-induced, stromally derived growth factor that might function as a progestomedin.