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Original Studies |
Department of Obstetrics and Gynecology, Yong-Dong Severance Hospital (B.-S.L.), Seoul, Korea; and Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, and Brigham and Women’s Hospital (R.A.N.), Boston, Massachussets 02115
Address all correspondence and requests for reprints to: Dr. Romana A. Nowak, University of Illinois, 1207 West Gregory Drive, Urbana, Illinois 61801. E-mail: ranowak{at}uiuc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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Transforming growth factors-ß (TGFßs) are multifunctional peptides that occur as five similar isoforms each encoded by a distinct gene (12). TGFß1, -2, and -3 have been identified in a variety of normal and transformed mammalian cells and tissues (12, 13). TGFßs exhibit diverse biological activities, including stimulation or inhibition of cell growth, differentiation, regulation of extracellular matrix production, and chemotaxis (12, 13). The biological activities of TGFßs in their target tissues are mediated through three specific cell surface receptors, designated receptor types I–III (14, 15). The type I and II receptors have been shown to be serine/threonine kinases, whereas the type III receptor, also called endoglin, appears to act primarily as a cell surface binding protein (15, 16).
TGFßs have been identified in the human female reproductive tract in the oviduct, endometrium, and myometrium (17, 18, 19). In the endometrium, TGFß messenger ribonucleic acid (mRNA) is found in both the glandular epithelial and stromal cells, with highest levels present during the late proliferative and early to midsecretory phases of the cycle (17). The mRNAs and proteins for TGFß1, -ß2, and -ß3 as well as for all three receptors have been detected in human myometrium and leiomyomas (19, 20). The TGFß2 isoform appears to be present in the lowest amounts, as the mRNA was detectable only by RT-PCR. In women undergoing GnRH agonist (GnRHa) therapy for treatment of leiomyoma tumors, there was a marked reduction in the expression of the mRNAs for TGFß1, TGFß3, TGFß type I receptor, and TGFß type II receptor in leiomyomas (21). These results suggest that GnRHa may cause leiomyoma regression through a mechanism involving TGFß.
Abnormalities in the TGFß ligand-receptor system have been implicated in a number of different fibrotic diseases (22). The goals of this study were to compare expression of TGFßs in matched pairs of myometria and leiomyomas and to examine the biological effects of TGFß1 and TGFß3 on cultured human myometrial and leiomyoma smooth muscle cells (SMCs). The two biological end points chosen for this study were cell proliferation, as measured by changes in DNA synthesis, and collagen production.
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Materials and Methods |
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Fibroid and myometrial tissues were obtained from 10 premenopausal women with symptomatic uterine fibroids at the time of elective hysterectomy and were not receiving any type of hormonal or drug therapy. Collection of tissues was obtained under a consent for use of discarded human tissue in accordance with the Brigham and Women’s Hospital policy. A portion of each tissue sample was immediately frozen at -80 C for subsequent RNA processing, and the remaining tissue was used for establishing primary cell cultures. Fixed tissue samples for each fibroid and myometrium were obtained from the Pathology Department at the hospital. Five of the patients were in the proliferative phase of the menstrual cycle at the time of their surgery, and five were in the secretory phase.
Cell culture
Fibroid and myometrial tissue were minced into 1- to 2-mm explants and placed in DMEM (Whittaker Bioproducts, Walkersville, MD) supplemented with 10% FBS (HyClone Laboratories, Inc., Logan, UT) and containing 200 U/mL collagenase (Life Technologies, Inc., Grand Island, NY). Myometrial tissue was digested for 8–10 h, and fibroid tissue for 18–20 h in a 37 C incubator. Dispersed cells were then centrifuged at 450 x g for 5 min, the resulting cell pellet was resuspended in DMEM plus 10% FBS, and the cells were plated in 75-mL culture flasks (Nunc, Naperville, IL). Cultures were maintained at 37 C in a humidified atmosphere of 95% air and 5% CO2. The purity of the cells was assessed as described in our earlier studies (23). Cells were used in experiments between passages 1–3.
The effect of increasing cell density on TGFß1 and TGFß3 production by cultured myometrial and leiomyoma SMCs was tested by plating various cell numbers ranging from 50,000–1,500,000 cells/dish in DMEM and 10% serum. The cells were given 2 days to attach and begin proliferating, at which time they were washed, and the medium was replaced with DMEM and 0.1% BSA. After 3 days, the conditioned medium was collected for measurement of TGFß1 protein levels using an enzyme-linked immunosorbent assay (ELISA), and cell extracts were harvested for processing to total RNA. Steady state levels of TGFß1 and -ß3 mRNAs were measured by Northern blotting. Three experiments were performed using cells from three different patients.
The effect of exogenously added TGFß1 and -ß3 on collagen production was tested using myometrial and leiomyoma SMCs that had been allowed to grow to 80% confluence in culture dishes. TGFß1 or TGFß3 (R and D Systems, Inc., Minneapolis, MN) was added at the following concentrations: 0, 0.1, 1.0, and 10.0 ng/mL in DMEM and 0.1% BSA. These concentrations were higher than the levels of endogenous TGFß1 measured in conditioned medium from the cells. Cells were treated for 24 h, after which they were harvested and processed to total RNA. Three experiments were performed using cells from three different patients.
The effect of a TGFß1–3 neutralizing antibody (Genzyme Corp., Cambridge, MA) on collagen production by myometrial and leiomyoma SMCs was also tested. Cells were plated in culture dishes and allowed to reach 80–90% confluence. At this time the cells were washed in DMEM and 0.1% BSA and cultured in this medium for 48 h to make them quiescent. The cells were then washed and cultured in DMEM and 0.1% BSA for an additional 24 h with one of the following treatments: no antibody, 10 µg/mL nonspecific mouse IgG, or 10 µg/mL of the anti-TGFß1–3 monoclonal antibody. Cells were then harvested and processed for RNA analysis. Two experiments were performed using cells from two different patients.
RNA and protein extraction
Total RNA was prepared from fresh tissue as described previously (24). Total RNA was extracted from cultured cells with TRIzol. In brief, cultured fibroid and myometrial cells were collected and dissolved in TRIzol using 1 mL TRIzol/dish, and 0.2 mL chloroform was then added to each tube. After centrifugation at 12,500 rpm for 15 min, the aqueous phase was collected and precipitated with isopropyl alcohol. The precipitate was washed with 75% ethanol and centrifuged at 9500 rpm for 5 min, and the resulting pellet was dried and then reconstituted.
Northern blots
Approximately 10 µg total RNA/sample were separated on a
1%(wt/vol) agarose gel containing 2.2 mol/L formaldehyde and then
transferred to nitrocellulose membranes (Schleicher & Schuell, Inc., Keene, NH). TGFß1, TGFß3, collagen type I (
1), and
collagen type III (1) mRNAs were detected using
32P-labeled cDNA probes generated with a specific
activity of approximately 1–2 x 106 cpm/ng
DNA, respectively. All of the cDNAs were obtained from American Type Culture Collection (Manassas, VA). Probes were labeled
using a random primers DNA labeling kit (Life Technologies, Inc.). The filters were prehybridized overnight at 42 C, then
hybridized for 18 h with approximately 10 million cpm of the
labeled cDNA probe. After hybridization, the filters were washed twice
at 42 C for 30 min in 2 x SSC (salt sodium citrate)-0.1% SDS and
once at 60 C for 30 min in 0.2 x SSC-0.1% SDS. Filters were
autoradiographed with an intensifying screen for 6 days at -70 C for
TGFß and 1–2 days for collagen. Autoradiographs were analyzed on a
scanning densitometer (Molecular Dynamics, Inc.,
Sunnyvale, CA) to quantitate differences in levels of transcripts of
each sample.
[3H]Thymidine incorporation assays
Fibroid and myometrial cells were plated in 96 wells at a density of 12,000 cells/well and cultured in DMEM and 10% FBS for 48 h. The cells were placed in DMEM and 1.0% FBS for 48–54 h, then received fresh DMEM and 1.0% FBS containing one of the following treatments: 0, 0.1, 1, or 10 ng/mL of TGFß1 or TGFß3 in the absence or presence of an immunoneutralizing monoclonal antibody to TGFß1–3 (2 and 20 µg/mL). The antibody was used to determine the specificity of TGFß1 and TGFß3 action on [3H]thymidine incorporation. Cells were treated with the growth factors for 24 h with the addition of 0.2 µCi/mL [3H]thymidine for the final 6 h of culture. Cells were then harvested and counted to measure the rate of incorporated [3H]thymidine. Three experiments were performed with 8 wells/treatment group/experiment.
Immunohistochemistry
Myometrial and leiomyoma tissues were fixed in 10% formalin for 8–12 h, dehydrated, embedded in paraffin blocks, and cut into 5-µm sections. Deparaffinized sections were first incubated with 1.5% goat serum/phosphate-buffered saline as a blocking step for 30 min at room temperature. Sections were then incubated with the rabbit polyclonal antibody to TGFß3 (Santa Cruz Biotechnologies, Inc., Santa Cruz, CA) for 1 h at room temperature at a concentration of 5 µg/mL. Control slides received the same concentration of nonspecific rabbit IgG. Binding was visualized using 5 µL/mL biotinylated goat antirabbit secondary antibody diluted in blocking solution followed by avidin/horseradish peroxidase binding (Vector Laboratories, Inc., Burlingame, CA). The complex was detected with diaminobenzidine (0.1%), and the sections were counterstained with hematoxylin for 1 min (Gill no. 2, Sigma, St. Louis, MO).
TGFß1 ELISAs
TGFß1 in conditioned medium from cultured cells was measured using a PREDICTA kit (Genzyme Diagnostics, Cambridge, MA).
Protein assays
Total cellular protein was measured using the bicinchoninic acid protein assay kit (Pierce Chemical Co., Rockford, IL). BSA was used as the protein standard.
Statistics
Analysis of differences in the levels of mRNAs for the TGFßs
(normalized to the level of -tubulin mRNA) was carried out using
Student’s t test. Statistical analysis of the proliferation
assays was performed using Kruskal-Wallis ANOVA with Dunn’s test using
the STATA software program (CRC, College Station, TX).
P < 0.05 was considered statistically significant.
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Results |
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, A and B). This increased expression
was observed in each of the 10 patients whose tissues were analyzed and
was not dependent on the stage of the menstrual cycle. Levels of
TGFß1 mRNA were similar among all patients, with no statistical
difference in the level of expression between leiomyomas and myometrium
(Fig. 1B). Immunohistochemical analysis of TGFß3 protein expression
in these same matched pairs of leiomyoma and autologous myometrium
showed a very intense immunoreactivity for TGFß3 in leiomyoma
tissues, whereas myometrial tissues showed only light immunostaining
(Fig. 2).
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and 4). The amount of TGFß1 secreted by
both myometrial and leiomyoma SMCs increased with increasing cell
density. Northern analysis of RNA from cultured cells plated at various
densities showed increased expression of both TGFß1 mRNA (Figs. 3 and 4) and TGFß3 mRNA (Fig. 5) with
increasing cell density.
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shows the results for TGFß1. The
results for each treatment group are expressed as a percentage of the
control group (no growth factor, no antibody). TGFß1 significantly
inhibited DNA synthesis at 0.1 ng/mL (41.7 ± 17.8%;
P < 0.01), 1 ng/mL (53.5 ± 11.9%;
P < 0.005), and 10 ng/mL (38.5 ± 25%;
P < 0.05) in myometrial cells. However, TGFß1 had no
effect on DNA synthesis by leiomyoma cells.
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TGFß3 significantly inhibited tritiated thymidine uptake by
myometrial cells at 1 ng/mL (31 ± 8%; P < 0.01)
and 10 ng/mL (42 ± 24%; P < 0.005; Fig. 7). In contrast, TGFß3 showed a
significant stimulatory effect on leiomyoma cells at 0.1 ng/mL
(132 ± 7%; P < 0.05), 1 ng/mL (140 ±
11%; P < 0.05), and 10 ng/mL (125 + 15%;
P < 0.05). Addition of the blocking antibody to
TGFß1–3 (2 or 20 µg/mL) in the presence of TGFß3 (0.1 and 1
ng/mL) blocked the inhibitory effect of TGFß3 on myometrial cells as
well as the stimulatory effect of TGFß3 on leiomyoma cells (Fig. 7).
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We therefore performed experiments to test the effects of a TGFß
immunoneutralizing antibody on collagen production by myometrial and
leiomyoma SMCs. The results from a representative experiment are shown
in Fig. 8. Treatment with the TGFß
antibody for 24 h caused a marked reduction in expression of
steady state mRNA levels for collagen type I (47–61%) in both
leiomyoma and myometrial SMCs. The steady state levels of collagen type
III mRNA were also reduced in both cell types (45–50%). Addition of a
nonspecific mouse IgG had no significant inhibitory effect on collagen
production.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of our study show that leiomyomas have a 5-fold increased expression of the mRNA for TGFß3 compared with autologous myometrial tissue. Leiomyomas also showed much more intense immunoreactivity for the TGFß3 protein than corresponding myometrium. In contrast, TGFß1 mRNA levels in fresh tissues and TGFß1 protein levels in cultured cells were similar for the two cell types. Similar findings were reported by Murphy et al. (20). These investigators also reported that leiomyomas show a greatly reduced level of expression of the TGFß type II receptor compared with myometrium. It is not known whether levels of TGFß receptors are influenced by the levels of TGFß ligand in uterine SMCs, but it is certainly one possible mechanism for regulation.
Both TGFß1 and TGFß3 production appear to be regulated by changes in cell density in vitro. Steady state levels of the mRNAs for both isoforms as well as levels of TGFß1 protein increased as the cell density of leiomyoma or myometrial SMCs increased. This would be expected if TGFß acts primarily as a growth inhibitor for these cells. We saw no differences in the levels of expression of the two TGFß isoforms with different stages of the menstrual cycle. However, a study by Dou et al. (21) reported that the levels of TGFß1, TGFß3, TGFß type I receptor, and TGFß type II receptor mRNAs were suppressed in leiomyomas of women who had received GnRHa therapy compared with those in leiomyomas from women who were untreated. These findings suggest that the TGFß ligand-receptor system in uterine smooth muscle may be at least partially under steroid hormone control, as treatment with GnRHa causes a suppression of circulating estradiol and progesterone levels to postmenopausal levels. Alternatively, it may be possible that the GnRHa has direct effects on leiomyoma SMCs.
The effects of TGFß1 and -ß3 on DNA synthesis by leiomyoma and myometrial SMCs were quite different. As anticipated, both TGFß isoforms inhibited DNA synthesis in myometrial SMC. However, the leiomyoma SMCs did not show any growth inhibition in response to TGFß1 and showed an increase in DNA synthesis when treated with TGFß3. One possible explanation for this difference in response between the two cell types may be that leiomyoma SMCs show a greatly reduced level of expression of the TGFß type II receptor (20). The type II receptor has been most closely associated with changes in cell proliferation, whereas the type I receptor appears necessary for induction of protein synthesis (28).
The loss of the antiproliferative response of leiomyoma SMCs to TGFß is similar to that observed for vascular SMCs from atherosclerotic lesions. A number of studies have shown that normal vascular SMCs are growth inhibited by TGFßs (29, 30, 31, 32, 33, 34). However, SMCs cultured from atherosclerotic plaques show an increase in DNA synthesis, proliferation, and collagen synthesis in response to TGFß1 (29, 30, 33). These SMCs also have greatly reduced levels of the TGFß type II receptor (29) and increased expression of TGFß1 (35). Transfection of vascular SMCs from atherosclerotic plaques with the TGFß type II receptor cDNA restored the normal growth inhibitory effects of TGFß in these cells (29).
Alterations in the TGFß ligand-receptor system have been implicated in the development of several other fibrotic diseases. In the kidney, fibrosis due to glomerulonephritis, diabetic nephropathy, or angiotensin-induced nephropathy is associated with elevated levels of TGFß1 in the glomeruli and increases in collagen, fibronectin and proteoglycans (36, 37, 38). Liver biopsy specimens from patients with liver fibrosis show elevated levels of mRNAs for both collagen and TGFß1. Immunostaining of the biopsy specimens showed that the TGFß1 protein was present in areas of fibrosis, but not in normal liver tissue (39). Pulmonary fibrosis in both rats and humans is also associated with increases in TGFß1 production by bronchoalveolar cells, which precede increases in collagen and fibronectin production (40). Our results showed that TGFß is important for collagen production by both myometrial and leiomyoma SMCs. Treatment of SMCs with a neutralizing antibody to TGFß caused a marked decrease in the steady state levels of the mRNAs for collagen type I and type III.
The results of our studies examining the effects of TGFß on DNA synthesis by myometrial and leiomyoma SMCs differ somewhat from those reported by Tang et al. (19). These investigators tested the effects of TGFß1, -ß2, and -ß3 on DNA synthesis by human myometrial SMCs. Cells were treated with the TGFßs in the presence of varying concentrations of serum ranging from 0–10%. Their results showed that TGFßs had no effect on DNA synthesis of the myometrial SMCs when the cells were cultured in either no serum or 10% serum. However, when SMCs were treated with TGFßs in the presence of 2% serum, there was a biphasic response to the added growth factors. At lower concentrations of TGFß (0.1–0.5 ng/mL) the SMCs showed an increase in DNA synthesis, but at the higher concentrations of TGFß (0.5–10.0 ng/mL) DNA synthesis was inhibited. We saw an inhibition of DNA synthesis in the myometrial SMCs at all concentrations of TGFß1 and -ß3 (0.1–10.0 ng/mL) while leiomyoma SMCs showed no inhibition in response to TGFß1 and an increase in proliferation in response to all concentrations of TGFß3. Our experiments were performed in the presence of 1% serum, and this could perhaps account for the differences in response seen at the lower concentrations of TGFß. Alternatively, it is also possible that differences in the numbers of cells plated per well or in the way in which the cells were made quiescent could also have altered the responses of the myometrial SMCs to TGFß.
In summary, we have shown that leiomyomas have increased expression of TGFß3 compared with autologous myometrium. In addition, leiomyoma SMCs show an altered response to the antiproliferative effects of TGFß. Further studies are needed to determine the mechanism for this altered response, particularly the role of the TGFß type II receptor.
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Footnotes |
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Received February 29, 2000.
Revised September 25, 2000.
Accepted October 18, 2000.
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