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Department of Obstetrics and Gynecology, CSMC Burns and Allen Research Institute (R.J.Z., S.R.W., D.A.M.), and University of California School of Medicine (R.J.Z., D.A.M.), Los Angeles, California 90048
Address all correspondence and requests for reprints to: Dr. Rob Zachow, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Davis Building, Room 2056, 8700 Beverly Boulevard, Los Angeles, California 90048-0750.
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hydroxylase/C17,20 lyase mRNA content was reduced 4.5-fold
in the presence of HGF. Thus, HGF is expressed in both TIC and GC
obtained from the immature rat ovary, suggesting its presence in
growing follicles. In TIC, HGF stimulated P4 synthesis, but
impaired androgen production, concurrent with a down-regulatory effect
on P45017 hydroxylase/C17,20 lyase gene
expression. Collectively, these results indicate that HGF reversibly
impairs LH-stimulated androgen production in TIC. Such effects may help
promote folliculogenesis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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hydroxylase/C17,20 lyase
(P45017). These enzymes catalyze the stepwise conversion
of cholesterol to progestins and, ultimately, androstenedione.
Importantly, androgen production by differentiated TIC must be
carefully regulated because premature production of androgens could
lead to apoptosis in GC (1, 2) and, hence, the demise of the
follicle. LH is the hormone principally responsible for stimulating TIC differentiation; however, studies have shown that intraovarian growth factors, cytokines, and steroids can promote or suppress the effects of LH on steroidogenic differentiation of TIC into androgen-producing cells (3, 4). No single intraovarian factor to date has been identified to be solely responsible for this important regulatory process. Indeed, genetic knockout experiments with a variety of growth and differentiation factors indicate that redundancy exists in the regulation of critical functions such as reproduction. It is uncertain whether a cohort of factors is indeed necessary, or whether an unidentified single regulatory factor governs TIC differentiation into androgen-producing cells.
Hepatocyte growth factor (HGF) is an 87-kDa cytokine initially characterized as an angiogenic factor that promotes DNA synthesis in primary epithelial cell cultures (5). Subsequent studies have shown that in addition to its mitogenic function, HGF induces cell motility (5); moreover, HGF messenger RNA (mRNA) is expressed in fetal and neonatal rat tissues (6) as well as human placenta (6). Hence, it has been suggested that HGF may have a role in regulating cell proliferation and differentiation during tissue development and remodeling (6, 7).
Recently, HGF mRNA has been detected in murine ovaries (8) and bovine TIC (9); in the adult mouse, the HGF receptor was found in growing follicles (10). Furthermore, HGF protein was detected in the conditioned medium from bovine TIC cultures (9). In bovine GC, HGF induced cell growth in vitro (9), and although prior studies have not determined whether HGF is present in the rat ovary, in cultured rat antral follicles HGF delayed the onset of apoptosis (11). Based on these studies, it is possible that in the recruited cohort of growing follicles, TIC-derived HGF acts locally to promote follicle maturation by 1) stimulating mitosis and 2) preventing apoptosis in GC. Because TIC androgen production is essential for ovulation, but aberrant androgen levels are detrimental to folliculogenesis (1, 2), there must be mechanisms in the ovary to prevent premature increases in androgen production. As the effects of HGF are consistent with a follicle growth-promoting role, this study was performed to determine whether HGF might be an intraovarian factor capable of reversibly suppressing TIC androgen synthesis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals
Immature female Sprague-Dawley rats (Harlan Industries,
Indianapolis, IN) were used in all studies. Rats from which TIC were
isolated were hypophysectomized by Harlan at 21 days of age. Rats
arrived on day 25 and were allowed water (containing 5% dextrose) and
food ad libitum. On day 26, rats were rendered unconscious
via CO2 inhalation and killed by cervical dislocation as
approved by the Cedars-Sinai animal care and use committee. Ovaries
were removed and placed in ice-cold medium 199 containing 25
mM HEPES and supplemented with 0.1% BSA (Sigma Chemical
Co., St. Louis, MO).
Cell culture
Theca-interstitial cells.
Highly purified populations of TIC
were obtained from the enzymatically dispersed ovaries of
hypophysectomized (Hx) rats via Percoll density gradient
centrifugation, as previously described (12). TIC (3.0–4.0 x
104 viable cells/200 µl final volume·well) were
cultured in 96-well culture plates. Control TIC were incubated in
McCoy’s 5a medium (M5a, serum-free and supplemented with 100 U/ml
penicillin, 100 mg/ml streptomycin sulfate, and 2 mM
L-glutamine) without hormones. Treatments consisted of LH
(0.003–3.0 ng/ml), HGF (0.1–100 ng/ml), or a combination of LH and
HGF. The range of HGF concentrations was chosen to bracket the reported
Kd (0.3 nM) for HGF binding in epithelial cells
in vitro (5). Cultures were terminated at 6–96 h (as
described below), and the culture-conditioned medium was collected and
stored at -20 C until RIAs for progesterone (P4) (13),
androstenedione (14), and androsterone (15).
To evaluate whether the effects of HGF were reversible, TIC were incubated in the presence of LH (0.3 ng/ml) and HGF (50 ng/ml) for 48 h, at which time culture-conditioned media were removed and frozen. The TIC were washed in situ with fresh M5a, then challenged with LH (0.3 ng/ml) for an additional 48 h (total of 96 h in vitro). Androsterone levels in culture-conditioned medium were measured by RIA.
GC.
To obtain GC for HGF mRNA expression studies, ovaries
were removed from 26-day-old intact rats, and GC were obtained by
follicle puncture as previously described (16). GC were washed via
centrifugation (3 min at 250 x g), and the GC pellet
was resuspended in M5a. Isolated GC were counted using a hemacytometer,
and cell viability was determined by the trypan blue exclusion method.
GC (4.0–5.0 x 104/200 µl final volume·well) were
cultured in 96-well plates for 48 h. Treatments consisted of FSH
(0.1 IU/ml) or HGF (50 ng/ml). Control GC were incubated in M5a without
hormones.
Determination of TIC viability and DNA content in the
presence of HGF
To determine the effect of HGF on cell viability, TIC were
incubated (as described above) in the presence and absence of LH (0.3
ng/ml), with and without HGF (50 ng/ml). At 48 h, culture media
were aspirated, and cells were washed with PBS, pH 7.0. Trypan blue
(10% trypan blue in M5a; 50 µl) was added to each well, and
approximately 100 cells were immediately counted (per field) in 4
fields/well under light microscopy (x20 magnification). The ratio of
viable (clear) cells to nonviable (blue) cells was determined.
To investigate the effects of HGF on DNA content in TIC cultures, cells were incubated in 96-well plates. TIC were challenged with LH (0.3 ng/ml), HGF (50 ng/ml), or both LH and HGF. At 48 h, the culture media were removed, the wells were washed with PBS, and the cells were scraped from the wells using a rubber policeman. Cells were pooled (5–6 x 105) according to treatment regimen, and DNA content was measured using a minidiphenylamine DNA assay as previously described (17). Viability and DNA content determinations were performed in two independent experiments.
Measurement of HGF and steroidogenic enzyme mRNAs
The presence of HGF mRNA was determined by reverse transcription
(RT) of cytoplasmic RNA extracts followed by amplification of specific
complementary DNA (cDNA) sequences by semiquantitative PCR, as
previously described (18). Briefly, TIC were incubated for 48 h
(as described above), with LH (0.3 ng/ml), HGF (50 ng/ml), or both LH
and HGF. GC were cultured in the presence of FSH (0.1 IU/ml) or HGF (50
ng/ml) with and without FSH. TIC and GC control groups received M5a in
the absence of hormones. To extract RNA, the conditioned media were
removed, and the cells were lysed and harvested by scraping in 50 µl
ice-cold RNA extraction buffer [140 mM NaCl, 1.5
mM MgCl2, 10 mM Tris-HCl (pH 8.0),
0.5% Nonidet P-40, 1 mM dithiothreitol, and 20
mM vanadyl ribonucleoside complexes]. Four replicate wells
were pooled, and RT was performed as previously described (18). For
PCR, oligonucleotide primers were synthesized in our lab (using an
Applied Biosystems model 391 DNA synthesizer, Foster City, CA) that
were previously shown to amplify a 290-bp region of the bovine HGF cDNA
sequence (9). The primers are completely homologous to bovine (9), rat
(19), and human (20) HGF cDNA. To control for variations in individual
PCR reactions, a mutant control HGF cDNA fragment was synthesized by
site-directed mutagenesis. In the HGF cDNA (19), a T was substituted
for a G at base 778 to introduce an EcoRI restriction site.
The resultant mutant HGF can be amplified by HGF primers, but can be
distinguished from the amplified wild-type HGF by restriction digestion
with EcoRI. The control cDNA (1 pg) was included in each
PCR, and all samples from each experiment were amplified at the same
time.
After 30 cycles of PCR in the presence of [32P]deoxy-CTP, the amplification products were digested by EcoRI to cleave the mutant control cDNA. After the restriction enzyme digestion, products were separated on a 2% agarose gel stained with ethidium bromide. The radiolabeled bands were excised from the gel and counted in a ß-spectrometer.
To verify that the PCR product was HGF mRNA, the 290-bp bands were cut from the gel, and DNA was extracted from the gel fragments using a Quiagen DNA extraction kit (Chatsworth, CA). The amplified region of the HGF gene contains a single StyI restriction digest site at base 811. Hence, aliquots of extracted PCR product were enzymatically digested with StyI for 3 h at 37 C and subjected to gel electrophoresis as described above. In addition, aliquots of the extracted DNA were sequenced using a silver sequencing kit obtained from Promega (Madison, WI).
To determine the effect of HGF on TIC steroid enzyme gene expression,
TIC were cultured without hormones (control) or with HGF (50 ng/ml) or
LH (0.3 ng/ml) in the presence and absence of HGF for 48 h. At
48 h, cultures were terminated, and RNA was extracted as described
above. P450scc, 3ßHSD, and
P45017 mRNA levels were measured using semiquantitative
RT-PCR as described previously by our lab (18, 21, 22).
Statistical analysis
Treatments were administered in triplicate, and each experiment
was repeated a minimum of three times. Mean values from independent
experiments were statistically analyzed by unpaired t test,
and multiple comparisons were analyzed using one-way ANOVA followed by
Tukey’s test. Values were determined to be significant when
P 
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, gel, upper
band). Furthermore, HGF was expressed in both the presence and
absence of gonadotropins or HGF (Fig. 1, gel, lanes 2–5, 7, and 8, and
lower panel). Partial DNA sequence analysis matched the
obtained 290-bp PCR product with a region of the reported sequence of
rat HGF. Furthermore, restriction digestion of the 290-bp PCR product
with StyI yielded the appropriate fragments of 109 and 191
bp (not shown). This is the first report showing expression of HGF mRNA
in the rat ovary and led us to determine role a for HGF in regulating
TIC steroidogenesis.
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In TIC cultures, LH stimulated a dose-dependent increase in
androsterone synthesis compared to controls (Fig. 2a).
At the maximal stimulatory concentration of LH (0.3 ng/ml),
androstenedione production was also stimulated over that of controls
(Fig. 2a, inset). HGF (50 ng/ml) did not alter basal
androsterone (Fig. 2a) or androstenedione (Fig. 2a, inset)
levels. At the lower concentrations of LH (0.003–0.03 ng/ml), HGF did
not affect LH stimulation of androsterone production. However, at 0.1
ng LH/ml and greater, HGF inhibited androsterone production. At the
maximal stimulatory concentration of LH (0.3 ng/ml), HGF suppressed
LH-dependent TIC androsterone production by more than 50% (Fig. 2a).
Moreover, the suppressive effects of HGF on LH-dependent androsterone
production were concentration dependent (IC50 = 1.5 ±
0.01 ng HGF/ml; Fig. 2b). To determine whether HGF selectively impaired
the synthesis of androsterone (by interfering with 4-ene-5-reductase
and/or 3HSD), or inhibited androgen production at the level of
P45017, androstenedione levels were also measured.
Results showed that LH-stimulated androstenedione production was
impaired by HGF (Fig. 2a, inset), and this indicated
generalized inhibition of LH-stimulated androgen production.
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), whereas
beginning at 36 h (Fig. 2c) and beyond LH-stimulated androsterone
levels were suppressed by HGF. Therefore, it appears that HGF did not
completely block TIC differentiation to the androgenic phenotype, and
this is supported by the fact that in the presence of HGF, LH-dependent
androstenedione and androsterone production remained significantly
above control levels.
TIC viability was not affected by HGF, demonstrating that HGF was not
cytotoxic to TIC (Table 1). Also, HGF did not alter DNA
content in TIC cultures, indicating that cell number was not altered by
HGF.
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). In the
presence of LH (0.1 and 0.3 ng/ml), HGF significantly augmented
P4 levels (Fig. 3a). Whereas in the absence of LH, HGF
(0.1–50 ng/ml) induced a moderate, but significant (P 0.05),
increase in P4 levels (Fig. 3b). Additional studies showed
that LH-stimulated P4 production was augmented by HGF in a
dose-dependent manner (EC50 = 0.3 ± 0.01 ng/ml; Fig. 3b). When TIC were challenged with 10 ng HGF/ml, LH-dependent
P4 levels were increased 2.6-fold (Fig. 3b). Interestingly,
at 100 ng HGF/ml, LH-dependent P4 production was
significantly reduced below that detected in cultures given LH without
HGF. This effect could result from a down-regulation or desensitization
of LH-induced signal transduction, such as observed in the sustained
presence of high levels of LH and/or cAMP (4).
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). However, after an additional 48 h in the
presence of LH without HGF (Fig. 4, 96 h), TIC androgen production
recovered and attained levels comparable to those present in TIC
challenged with LH (in the absence of HGF) for the entire 96-h culture
duration. This is an important finding and demonstrates that the
androgen-suppressive effects of HGF in TIC are reversible.
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mRNA expression. Results showed that HGF did not
affect basal or LH-dependent levels of P450scc
and 3ßHSD mRNAs (Fig. 5, a and b). Although basal
P45017 mRNA levels were not altered by HGF, LH-dependent
P45017 mRNA content was reduced by approximately
4.5-fold in the presence of HGF (Fig. 5c). Although the HGF stimulation
of P4 levels cannot be explained by increased
P450scc and/or 3ßHSD mRNA expression in TIC,
these results indicate that HGF-induced suppression of TIC androgen
production is most likely mediated at least in part by a selective
reduction in the expression of P45017, the rate-limiting
enzyme in the conversion of P4 to androgens.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TGF) or
keratinocyte growth factor) that have been shown to exert potent
regulatory effects on ovarian cell growth and/or steroidogenesis (9, 24). This strongly suggests that the overlap of growth factor-mediated
steroid regulatory effects in TIC ensures the proper and timely onset
of both androgen and P4 production. Because of the distinct
effects of HGF in TIC cultures, it is likely that HGF may work in
concert with other previously characterized growth factors and
cytokines (25) to suppress the synthesis of P45017 and
consequently retard androgen production by TIC surrounding preantral
follicles. If this is the case, premature androgen production would be
blocked, with subsequent benefit to the preantral follicles.
This study extends prior findings which have indicated that HGF is
involved in promoting follicle maturation due to its mitogenic (9) and
antiatretogenic effects (11). For example, it has been shown that HGF
prevented the onset of atresia in antral follicles obtained from
27-day-old rats (11); importantly, elevated follicular androgen levels
can induce apoptosis and follicular atresia (1, 2). The manner by which
HGF slowed atresia in the aforementioned report was not determined;
however, the present studies showed that HGF impaired LH-stimulated
androstenedione and androsterone synthesis in TIC, concurrent with a
reduction in P45017 mRNA levels. HGF suppression of TIC
androgen production could be one mechanism by which HGF prevents the
onset of apoptosis.
In contrast to its inhibitory effect on TIC androgen synthesis, HGF
stimulated basal and LH-supported P4 production by TIC, and
this effect could not be attributed to HGF-induced alterations in the
expression of P450scc and 3ßHSD mRNAs. One
likely mechanism is that decreased metabolism of P4 to
androgens in the presence of HGF caused an increase in the accumulation
of P4 in the culture medium. A selective inhibitory effect
on TIC androgen production is not without precedent in the ovary, and
indicates an important regulatory mechanism. For example, TGF
suppresses P45017 mRNA expression and androgen
production, but increases 3ßHSD mRNA levels in TIC (26). TGFß
selectively impairs androgen levels by specifically reducing
P45017 activity (27). Furthermore, TGFß augments
LH-stimulated P450scc content, concomitant with
potentiating LH-dependent P4 production in TIC (28).
Finally, in the presence of tumor necrosis factor-, LH-stimulated
androstenedione production as well as P45017 protein and
activity are reduced, but P4 production is not affected
(29). Thus, P45017 is a common site of regulation, but
none of the growth factors, including HGF, affects TIC in quite the
same manner. This indicates that the control of TIC differentiation and
androgen production is highly regulated and apparently fine-tuned by
ovarian peptides that potentially operate through several intracellular
mechanisms. The degree of growth factor-mediated redundancy is
consistent with the concept that regulation of P45017 is
critically important for reproductive success.
The HGF receptor is present in developing and mature follicles in the adult mouse (10); thus, it is likely that follicles at early stages of development can respond to HGF. However, temporal regulation of HGF expression by intact growing follicles has not been investigated. The present study showed that neither HGF nor gonadotropins blocked HGF mRNA expression in isolated TIC and GC in vitro. Although these data suggest that LH, FSH, and HGF may not alter HGF mRNA levels, this is not conclusive evidence that HGF gene expression is unaltered by in vivo hormone dynamics. It is important to consider that nothing is presently known about the control of ovarian HGF synthesis in vivo. In other systems, it has been demonstrated that E2, TGFß1, and glucocorticoids can affect HGF mRNA expression (8, 30). Although the significance of these observations for ovarian follicle development is unknown, the observation that E2 can block HGF mRNA expression raises the intriguing possibility that E2 could be a physiological signal to suppress intrafollicular HGF production. HGF could be involved in suppressing TIC androgen production until the GC begin to produce E2. The E2 would then block HGF production and release the TIC from HGF-directed inhibition. Androgen synthesis would increase, and the follicle could then secrete the large amounts of E2 necessary to trigger ovulation. Further studies will be required to determine the temporal pattern of HGF production in developing follicles and the physiological role of HGF.
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Acknowledgments |
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Footnotes |
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Received September 20, 1996.
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References |
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-androstane-3,17ß-diol and
5-androstane-3ß,17ß-diol. Steroids 30:679–689[CrossRef][Medline]
-hydroxylase messenger ribonucleic acid expression by luteinizing
hormone and insulin-like growth factor-I. Endocrinology 132:1945–1951-androstane-3,17ß-diol as a principal
metabolite of pregnenolone in rat ovary at onset of puberty. Nature 228:866–868[CrossRef][Medline]
inhibition of luteinizing hormone-stimulated androgen
production by ovarian theca-interstitial cells: mechanism of action.
Endocrine 3:415–420
-hydroxylase
activity by a direct non-competitive mechanism. Endocrinology 137:166–174[Abstract]
modulates luteinizing hormone-directed cytochrome
P45017-hydroxylase/C17–20 lyase in ovarian
theca-interstitial cells in vitro. Endocrine 2:625–631
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