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Department of Orthopedic Research (J.D.S., H.D., R.M.H., R.T.T.) and Biochemistry and Molecular Biology (R.T.T.), Mayo Clinic, Rochester, Minnessota 55905
Address all correspondence and requests for reprints to: Russell T. Turner, Ph.D., Mayo Clinic, Department of Orthopedics, Medical Science Building 3–69, 200 First Street SW, Rochester, Minnesota 55905. E-mail: rolbiecki.lori{at}mayo.edu
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0.05) between ovariectomy and ICI treatment
for cancellous bone area and labeled bone perimeter. ICI increased
skeletal indices of bone turnover in the cancellous bone of
ovary-intact rats but reduced these indices of bone turnover in the
cancellous bone of ovariectomized rats. The increase in bone turnover
was associated with a reduction in cancellous bone area in the
ovary-intact rats. A reduction in bone turnover was similarly
associated with an increase in bone area in the ICI-treated
ovariectomized rats. In summary, ICI exhibited complete estrogen
antagonism in cortical and cancellous bone, partial agonism in
cancellous bone, and no activity on tibial longitudinal growth rate of
growing ovary-intact rats. The effects in adult rats were influenced by
circulating levels of estradiol. ICI had no activity on body weight and
complete antagonism on uterine weight. These results demonstrate that a
ligand with high binding affinity to the estrogen receptor(s) can
elicit an array of estrogen-mediated regulation of bone metabolism. |
Introduction |
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Because of their high binding affinity and their lack of estrogen agonism, these estrogen antagonists have great potential as clinical chemoagents for breast cancer. The ability of ICI 182,780 (ICI) to inhibit cell growth, in fact, has been reported in MCF-7, as well as Br10 human breast cancer cells (3). The effectiveness of the C7 alkyl-substituted compounds in chemotherapy contrasts with tamoxifen, a pharmaceutically-developed antiestrogen of a triphenylethylene structure. Tamoxifen is the chemoagent of choice for defense in breast cancer (7, 8, 9, 10). Tamoxifen though possesses partial estrogen agonism in reproductive tissue. It is this degree of agonism that is thought to contribute to the acquired tolerance of breast tumor cells after extended tamoxifen therapy (4, 11). Antiestrogens with complete absence of estrogen agonism, on the other hand, may be more rapid, more potent tumorstatic agents with longer lasting results (4, 12).
In addition, the variable display of estrogen agonism by antiestrogens seems to be tissue-specific. A potential mechanism for the tissue-selectivity of antiestrogens involves differential transactivational gene transcription by the estrogen receptor (13). The model proposes that capacity of the ligand-bound estrogen receptor to activate gene transcription is mediated by two distinct regions within the receptor molecule. Analogs of different antiestrogen classes could confer conformational changes to the estrogen receptor, thereby affecting the interaction, either positively or negatively, between the ligand-bound estrogen receptor and DNA. Alternatively, a second type of estrogen receptor, the estrogen receptor-ß, could account for tissue differences based on variable tissue distributions of receptors (14). Because of the tissue-selectivity and the variable degree of agonism in antiestrogens, it is important to investigate the tumorstatic estrogen analogs, in terms of their side effects in nontumor, estrogen-responsive tissues. There are reports that these compounds may have detrimental effects on the skeletal system (15).
Estrogen has similar effects on the rat and human skeletons, and the response of the laboratory animal model to estrogen antagonists has successfully predicted the outcome in women (16). Thus, we investigated the effects of the ICI on skeletal tissue of female rats that were growing or sexually mature and either with or without ovaries.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1. Forty 10-week-old female Sprague-Dawley rats (Harlan, Indianapolis, IN) were used to evaluate the effects of ICI on skeletal growth and modeling. Thirty of the rats were divided into three groups of ovary-intact rats (n = 10): one group was injected with ICI, the second group was injected with the sesame oil vehicle, and the third served as the baseline control group. The baseline group was killed at the start of the treatment. A fourth group (n = 10) was ovariectomized 1 week before the start of the study (OVX group). ICI powder (Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK) was resuspended in 95% ethanol to a 100 mg/ml Stock Solution. Each day, an aliquot of the stock solution was resuspended in sesame oil and sonicated for the delivery of a 1.5-mg/kg BW dose of ICI, based on an averaged weekly weight of rats for the 3-week study. A vol of 0.1 ml was injected sc at the back of the neck. Ovariectomized rats were injected with vehicle. The fluorochrome tetracycline (20 mg/kg; Sigma Chemicals, St. Louis, MO) was injected at the base of the tail on the first day of treatment (day 1) and 2 days before death (day 19). Another fluorochrome calcein (20 mg/kg; Sigma Chemicals, St. Louis, MO) was similarly injected 9 days before death (day 13). Rats were anesthetized by CO2 inhalation and killed by guillotine decapitation. Wet weights of uteri were recorded. Tibiae were removed and fixed by immersion in 70% ethanol.
Exp 2. Rats which were either ovariectomized or ovary-intact were treated with either ICI or vehicle. Forty female Sprague-Dawley rats (Harlan, Indianapolis, IN) at 6 months of age, were divided into 4 groups of approximately 10 (±2) rats each. Two groups were ovariectomized 1 week before the start of treatment, and the other groups remained ovary-intact. One ovariectomized group and one ovary-intact group were treated groups and injected with ICI; the other ovariectomized and ovary-intact group were treatment controls and injected with vehicle. A small group of ovary-intact rats (n = 6) was killed on the first day of treatment. The bone fluorochrome tetracycline (20 mg/kg; Sigma Chemicals, St. Louis, MO) was injected at the base of the tail on the first day (day 1) of the 8-week study and 2 days before death (day 54). The bone fluorochrome calcein (20 mg/kg; Sigma Chemicals, St. Louis, MO) was similarly injected 12 days before death (day 44). The averaged body weight of the rats was recorded weekly. An aliquot of a 5% wt/vol stock solution of ICI in sesame oil (Zeneca Pharmaceutical, Macclesfield, Cheshire, UK) was diluted further in sesame oil for delivery of a 1.5-mg/kg·day dose, based on the weekly averaged body weight. As in Exp 1, a 0.1-ml vol was injected sc at the back of the neck daily throughout the 8-week study. Rats were anesthetized by CO2 inhalation and killed by guillotine decapitation. Blood was drained from the carcass, clotted, and centrifuged for serum isolation. Serum aliquots were stored at -80 C before assay. Wet weights of uteri were recorded. Tibiae were removed and fixed by immersion in 70% ethanol.
Exp 3. Skeletal effects were evaluated in 8-month old ovary-intact female Sprague-Dawley rats (Harlan, Indianapolis, IN), treated for 52 days with ICI (n = 7). Rats were injected sc with ICI (Zeneca Pharmaceutical, Macclesfield, Cheshire, UK) or sesame oil vehicle (1.5 mg/kg BW ICI). Rats were anesthetized by Ethrane inhalation and killed by exsanguination. Blood was obtained from the abdominal aorta. Tibiae were harvested and fixed, as in previous experiments, for cancellous bone histomorphometry.
Bone histomorphometry
Measurements for Exp 1 and 2 were performed with an
SMI-Microcomp semiautomatic image analysis system (Southern Micro
Instruments, Inc., Atlanta, GA), which consists of a Compaq computer
with microcomp software interfaced with a microscope and image analysis
software. Measurements for Exp 3 were executed as for Exps 1 and 2,
except for the image analysis software (OsteoMetrics, Inc., Atlanta,
GA). Skeletal indices are measured by registering the movement of a
digitizing pen across a graphics tablet as a tracing is superimposed on
an image of the section displayed on the video screen. As regions of
interest are traced in the bone specimen, the computer software records
the lengths of tracings and calculates the enclosed areas.
Cortical bone measurements. All cortical bone measurements of Exp 1 were made on unstained cross-sections obtained from the tibia-fibula synostosis using a low-speed saw equipped with a diamond wafer blade (Isomet, Buehler, Lake Bluff, IL). Cross-sections (150 µm) were ground to 15–20 µm on a roughened glass plate and permanently mounted. Fluorochrome labeling was visualized under reflected UV light. Cortical bone histomorphometry included cross-sectional area, medullary area, cortical area, periosteal bone formation rate, and periosteal mineral apposition rate and were performed as previously described (17), except for a bone growth period of 21 days.
Cancellous bone measurements. Proximal tibial metaphyses were dehydrated in 95% ethanol for 1 day, followed by 6 days in 100% ethanol before embedding, without demineralization, in a mixture of methylmethacrylate-2-hydroxyethyl-methacrylate (12.5:1). Parasagittal sections were cut from the middle of the proximal tibia (5 µm thick) with a Reichert Jung microtome.
All measurements, except for longitudinal growth rate, were conducted in a standard sampling site located in the secondary spongiosa of the metaphyseal region of the proximal tibia. This sampling site was located 1 mm from the most distal point of the epiphyseal growth plate, extended bilaterally, but excluded endocortical bone and encompassed a 2.88-mm2 tissue area (TAr). Mean longitudinal growth rate was determined as the distance from the calcein label to the metaphyseal growth plate cartilage at five equidistant sites across the growth plate. The mean distance was divided by the growth period of 9 days.
The following indices were obtained or calculated from measurements performed in the metaphyseal sampling site, as previously described (17), and according to Parfitt et al. (18): cancellous bone area, cancellous bone perimeter, labeled bone perimeter, mineral apposition rate, bone formation rate, and osteoclast-covered perimeter. Indices of cancellous bone architecture, such as trabecular number, trabecular thickness and trabecular separation, were estimated according to standard formulas (19).
Serum measurements
Measurements of 17ß-estradiol in Exp 3 were made using a
double-antibody RIA that has a minimum detectable limit of 1.4 pg/ml
(Diagnostic Products Corporation, Los Angeles, CA). Cholesterol
measurements in Exp 2 were measured by the Immunochemical Core Facility
at the Mayo Clinic using an automated procedure (Roche Diagnostic
System, Los Angeles, CA).
Statistical analysis
Comparisons between multiple pairs of groups were accomplished
by application of Fisher’s protected least-significant difference
(PLSD) post hoc test, after determination of significance by
one-way ANOVA (Exp 1). Two-way ANOVA was performed to determine whether
there is a significant effect of either ovarian status or ICI treatment
or whether there is a significant interaction between the two factors
(Exp 2). Subsequently, one-way ANOVA, followed by multiple-group
comparisons with Fisher’s PLSD, were conducted to determine the
significance of ICI treatment in the ovary-intact and in the
ovariectomized rats. Student’s t test was performed for
comparisons between ovary-intact control and ICI-treated rats (Exp 3).
Statistical significance was considered at P values
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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).
Exp 2. Ovariectomy increased final body weight, but there was
no interaction of ovariectomy and ICI, by two-way ANOVA, on final body
weight (Table 1). Two-way ANOVA revealed no effect of ovariectomy, a
significant effect of ICI, and a significant interaction between
ovariectomy and ICI on serum cholesterol levels. ICI significantly
increased serum cholesterol in ovary-intact (25%) but not in
ovariectomized rats (2%) (see Table 3).
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0.0001).
Serum 17ß-estradiol was not detectable in ovariectomized rats.
Skeletal data
Exp 1. ICI had no effect on cross-sectional area, medullary
area, and cortical area measured at the tibia diaphysis, whereas
ovariectomy and ICI similarly increased rates of mineral apposition and
bone formation measured at the same site (Table 2). Ovariectomy increased longitudinal
growth at the proximal tibial metaphysis in the young rats, whereas ICI
treatment of intact rats had no effect on longitudinal growth rate
(Fig. 1).
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0.01-.0005), increased
the percent of osteoclast-covered perimeter (Fig. 2), and decreased indices of cancellous
bone volume (bone area, trabecular number), had no effect on trabecular
thickness, and increased trabecular separation (Table 3). ICI had no effect on labeled bone
perimeter and on bone formation rate but decreased mineral apposition
rate. However, there was an interaction between ovarian status and ICI
on the labeled bone perimeter, such that ICI increased labeled
perimeter in ovary-intact rats and decreased this measurement in
ovariectomized animals. Neither of these effects was significant in
group comparisons after one-way ANOVA. As presented in Table 3 and Fig. 2, significant interaction between ovarian status and ICI was evident
for cancellous bone area (BAr/TAr), bone-forming perimeters (LPm/TPm),
and osteoclast-covered perimeter (OcPm), and for the architectural
indices of trabecular number (TbN) and separation (TbSp),
i.e. the direction of ICI’s actions was dependent on
ovarian status (Table 3 and Fig. 2). ICI decreased measurements related
to bone volume and bone-forming surfaces in ovary-intact rats but
increased these values in the ovariectomized rats.
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). ICI increased the percent of
double-labeled perimeter (63.8 ± 11.3 mm ICI vs.
14.6 ± 4.1 mm vehicle, P 0.001) and the rates
of mineral apposition (1.28 ± 0.11 µm/day ICI vs.
0.97 ± 0.15 µm/day vehicle, NS) and bone formation (89.4
± 12.7 mm2/day x 10-3 ICI
vs. 36.2 ± 10.2 mm2/day x
10-3 vehicle, P 0.001) at the
periosteal surface of cortical bone of ovary-intact rats.
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Discussion |
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and ERß (14). Early
investigations failed to detect any transcriptional activity in the
estrogen receptor-ICI complex, suggesting that the ICI-bound receptor
is unproductive and implying that ICI functions as a pure estrogen
antagonist. As a consequence, the observed skeletal response to ICI in
the rat was unanticipated.
ICI’s effects on the uterus, however, are consistent with previous
reports. ICI resulted in uterine atrophy comparable with ovariectomy in
ovary-intact rats and had no uterotrophic activity in the
ovariectomized rat. These findings are in agreement with the results of
Lundeen et al. (20), who reported that ICI, itself,
displayed no uterotrophic activity in the ovariectomized rat but
blocked uterine stimulation by 17-ethynyl estradiol when
administered together. These effects of ICI contrast with those of
triphenylethylene and benzothiophene antiestrogens, which, besides
being competitive inhibitors of estradiol, possess partial uterotrophic
activity (20).
In addition, ICI contrasts with the nonsteroidal antiestrogens in its effects on body weight. Ovariectomy increases body weight (21, 22), and estrogen replacement therapy prevents this change (21, 22, 23), which is similarly mimicked by tamoxifen (17, 24) and raloxifene (22). This weight gain is associated with increased food consumption, exhibits a predominant accumulation of fat, but cannot be completely prevented by matching the food intake of ovariectomized rats to the amount ingested by ovary-intact animals (21, 23). The change in body weight, therefore, suggests an alteration in metabolism. The exact mechanism of body weight increase is unclear, although it is under central regulation (25). ICI had no influence on the expected weight changes after ovariectomy. Our observation was similarly noted by Wakeling (3), which he attributed to the failure of ICI to cross the blood-brain barrier (26).
The effects of estrogen and estrogen deficiency on serum cholesterol in the rat model have been recently characterized (20). Triphenylethylene and benzothiophene antiestrogens have similar levels of estrogen agonism on bone and serum cholesterol (20). We investigated the effects of ICI on serum cholesterol, but results are inconclusive. Though ovariectomy did not increase serum cholesterol in this study, ICI increased serum cholesterol when given in the presence of ovaries. An effect of ovariectomy on serum cholesterol is not always seen in our laboratory (27) or in others (28). In one instance, we observed an increase in serum cholesterol in ovariectomized rats (22), whereas in another study, we saw no change (27). Estrogen’s regulation of circulating cholesterol levels in the rat involves a complex array of processes, many of which remain to be defined (20). We and others, however, have seen a consistent reduction of circulating cholesterol in ovariectomized rats treated with estrogen, triphenylethylene, and benzothiophene antiestrogens (20, 22, 27, 28). In this study, ICI had no effect on circulating cholesterol in the ovariectomized rat when analyzed by one-way ANOVA.
The skeletal effects of ovariectomy and estrogen replacement have been well characterized in the rat (21, 23, 29, 30, 31). The ovariectomized reference groups in this study consistently displayed the skeletal effects of estrogen deficiency (21, 23, 29, 30, 31, 32) at the examined sites in the tibia. The anticipated increases in radial and longitudinal bone growth and cancellous osteopenia were all manifested. The cancellous bone of the adult ovariectomized rat exhibited increased indicies of bone turnover (30, 31, 33).
Young ovary-intact rats were selected specifically to investigate the effects of ICI on bone growth. Radial and longitudinal bone growth normally change with age in parallel and both are inhibited by estrogen (23, 34). ICI increased the periosteal bone formation and mineral apposition rates in growing ovary-intact rats to a magnitude nearly identical to ovariectomy, indicating that the drug is a potent estrogen antagonist on the periosteum.
Paradoxically, ICI did not influence longitudinal bone growth in parallel to its effects on radial bone growth. Longitudinal bone growth occurs as a result of proliferation and hypertrophy of cartilage cells in the growth plate (35), whereas radial bone growth is determined by the number and activity of osteoblasts at the periosteal surface (36). Our results suggest that estrogen either does not act to regulate longitudinal bone growth via an estrogen receptor-mediated pathway or that ICI does not have access to estrogen target cells in the growth plate. The growth plate is avascular, and it is possible that there are differences in the ability of ICI and natural estrogens to diffuse through the extracellular matrix that separates chondrocytes. We recognize, however, that the effect of estrogen deficiency by ovariectomy on longitudinal growth rate is, itself, transient (28, 29) and subsides generally by 6 weeks after surgery.
Older animals, however, were used exclusively for measurements of remodeling in cancellous bone of the tibia (37). The rates of radial or longitudinal bone growth measured in the older rats of Exps 2 and 3 were very low, which reflects the skeletal maturity of these animals. We only reported data on radial and longitudinal growth from the young animals, because formation rates could be more accurately determined.
In the mature rats, we observed that the effects of ICI on cancellous bone mass and most indices of bone remodeling depended on gonadal status. The effects of ICI on cancellous bone area, labeled bone perimeter, trabecular number, trabecular separation, and osteoclast-covered perimeter were consistent with a potent estrogen antagonist in the presence of significant levels of serum estrogen, as found in ovary-intact rats. In the ovariectomized rat, where serum estrogen is significantly less, ICI behaved as a weak partial estrogen agonist on the same indices of cancellous bone architecture and turnover. Gallagher et al. (15) also show a detrimental effect of ICI on cancellous bone volume in growing sham-operated rats, but the actions of ICI on cancellous bone volume in ovariectomized rats were not investigated. The observations of our study led us to the inescapable conclusion that, in contrast to the reproductive tissues, ICI is not a pure estrogen antagonist in bone, and ICI seems to be capable of transcriptional activation.
This conclusion is further supported by the observed changes in the cancellous mineral apposition rate. The mineral apposition rate generally reflects osteoblast activity, whereas the previously discussed labeled perimeter reflects osteoblast number (36). Ovariectomy results in a small increase in the mineral apposition rate, which is prevented by treatment with estrogen (32, 38, 39). The observed reduction in the mineral apposition rate of ovary-intact rats and the reducing trend observed in the ovariectomized rats indicate that the actions of ICI on osteoblast activity are of an estrogen agonist. These observations suggest that ICI differentially influences the estrogen-regulated pathways that mediate the hormone’s actions on osteoblast number and activity.
The bone formation rate, for instance, is the product of osteoblast number and activity. Ovariectomy results in increases in the number and activity of osteoblasts and, as a consequence, leads to a large increase in the bone formation rate. In contrast, ICI was primarily an estrogen antagonist on osteoblast number and an estrogen agonist on osteoblast activity. As a consequence of the two opposing tendencies, ICI had no net effect on the calculated bone formation rate. We did not measure bone resorption, but a measurement of osteoclast-covered perimeter indicates that ICI was a estrogen agonist on osteoclast number in the ovariectomized rats. And, though there is only a tendency for osteoclasts to be increased by ICI in the ovary-intact rat, the observed osteopenia, without an accompanying reduction in bone formation, implicates an elevation in bone resorption.
If ICI were unable to activate transcription when bound to the estrogen receptor in reproductive tissues, then the observed estrogen agonism of ICI on bone would be through a nonestrogen receptor-mediated pathway. Nongenomic effects of the hormone have been described in other target tissues (40). However, transcriptional regulation by ICI has not been ruled out as a mechanism. Alternatively, transcriptional activity by antiestrogens of different classes is dependent on cell and promoter context (13). We have recently demonstrated that estrogen results in differential regulation of the same genes in bone and uterus (41). There are reports that ICI 164,384 induces AP-1 promoter activity (42), as well as of TGFß3 in human osteosarcoma (43). Additionally, ICI up-regulates quinone reductase expression in MCF-7 human breast cancer cells (44). Although gene regulation by ICI in bone still needs more detailed examination, these reports add credence to the assertion that an antiestrogen can induce an estrogen receptor-mediated effect.
In summary, our results demonstrated that ICI, though having no uterotrophic activity, displays the full spectrum of estrogen agonism and antagonism on bone metabolism, actions which are highly dependent on circulating estrogen levels. The mechanisms for these complex effects of ICI on bone remain to be identified.
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Acknowledgments |
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Footnotes |
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Received November 6, 1997.
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and ß. Endocrinology 138:863–870 and Erß at AP1 sites. Science 277:1508–1510This article has been cited by other articles:
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