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J. L. Pettis Veterans Administration Medical Center and Loma Linda University (C.R., D.J.B., S.M.), Loma Linda, California 92357; and Roche Diagnostics Boehringer Mannheim GmbH, Pharma Research, Bone Metabolism, Am Nonnenwald (K.L., C.D.), D-82372 Penzberg, Germany
Address all correspondence and requests for reprints to: Subburaman Mohan, Ph.D., Musculoskeletal Disease Center, J. L. Pettis Veterans Administration Medical Center, 11201 Benton Street (151), Loma Linda, California 92357. E-mail: mohans{at}llvamc.va.gov
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Introduction |
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Both IGF-I and IGF-II are produced by osteoblasts, and their mitogenic effects are mediated by their binding to the IGF plasma membrane receptors. The IGF type 1 receptor, which binds both IGF-I and IGF-II, appears to be the predominate receptor involved in mediating the effects of these growth factors in most cell types, including osteoblasts (10, 11). IGF-binding proteins (IGFBPs) modulate the actions of secreted IGFs by binding to them and increase the IGF half-life in the extracellular milieu and circulation by sequestering them in this bound form. IGFBPs either enhance or inhibit IGF actions on target cells (12, 13); in bone, the individual IGFBPs either inhibit or potentiate IGF effects on osteoblasts (4, 12, 13, 14, 15, 16, 17). Of the various IGFBPs secreted by bone cells, rhIGFBP-5 has several unique features that suggest that it is a key component of the IGF system in bone. rhIGFBP-5 is the most abundant IGFBP stored in bone, having a high specific binding affinity for hydroxyapatite and extracellular matrix proteins, therefore fixing it and its bound IGFs within bone (18, 19, 20). We have previously proposed that the local release of these sequestered IGFs and rhIGFBP-5 in bone could provide the mechanism by which osteoclastic bone resorption during remodeling gives rise to a coupled increase in bone formation. Therefore, the significant age-related decline in the skeletal content of IGF-I, which is positively correlated with decreasing rhIGFBP-5, could contribute in part to the age-related impairment in the coupling of bone formation to resorption (18, 19, 21).
rhIGFBP-5 is also unique, in that it is the only IGFBP that has been shown to consistently stimulate osteoblast cell proliferation in vitro (20, 22, 23, 24), thus increasing the number of osteoblasts. Recent studies suggest that the mitogenic effects of rhIGFBP-5 may in part be independent of IGFs and mediated through rhIGFBP-5’s own signal transduction pathway (14, 25). Because bone formation is dependent not only on the number but also on the activity of osteoblasts, in this study we evaluated whether recombinant human rhIGFBP-5 (rhIGFBP-5) also increases the activity of osteoblasts in vitro. Based on our findings that rhIGFBP-5 treatment increases osteoblast cell activity [increases osteocalcin production and alkaline phosphatase (ALP) activity], we further investigated the effect of rhIGFBP-5 on bone formation in an intact animal model.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vitro experiments
Cells were grown at 37 C in humidified incubators with 5%
CO2. For osteocalcin experiments, conditioned medium was
collected from serum-free (DMEM-0.1% BSA) cultures of MG63 or normal
human bone cells treated with various concentrations of rhIGFBP-5 and
10-8 M
1,25-(OH)2D3. This conditioned medium was
frozen at -70 C until assayed for osteocalcin by specific RIA (27),
the cells were extracted, and this extract was assayed for protein
concentration (28).
For ALP activity experiments, serum-free (DMEM-0.1% BSA) cultures of MG63 or normal human bone cells were treated with various concentrations of rhIGFBP-5 in the presence or absence of 10-8 M 1,25-(OH)2D3. The cell lysate was assayed for ALP activity (29).
In vivo experiments
Seven-week-old BALB/c or C3H/HeJ inbred mice were used for the
in vivo experiments. The animals were housed in a controlled
environment with 12-h light, 12-h dark cycles at 70 F, with food and
water ad libitum. In each experiment the treatment was
injected sc at the nape of the neck of each mouse at the same time each
day (0900 h). The vehicle used throughout was 150 mM
arginine phosphate buffer, pH 7. When IGF-I and rhIGFBP-5 were
administered together, IGF-I and rhIGFBP-5 were mixed and allowed to
incubate at room temperature for 1 h before administration so as
to form an IGF-I/rhIGFBP-5 complex before administration. Size
separation of this IGF-I/rhIGFBP-5 complex showed that more than 80%
of the IGF-I eluted in the 50-kDa fractions, suggesting that the
majority of the IGF-I exists as a complex in the IGF-I/rhIGFBP-5
treatment solution. The mice were killed with ethrane and decapitated.
Blood and both femurs were collected and used for biochemical
measurements of bone turnover. The experimental procedures performed in
this study are in compliance with the NIH Guide for the Care and Use of
Laboratory Animals. All animals studies were reviewed and monitored by
the animal studies subcommittee at the Jerry L. Pettis Veterans
Administration Medical Center (Loma Linda, CA).
Exp 1. BALB/c mice were divided into three groups of eight animals each. Group 1 received vehicle, group 2 received 13 µg/day IGF-I, and group 3 received 50 µg/day rhIGFBP-5. All groups received treatment for 20 days. The 13 µg/20 g mouse dose of IGF-I (7.7 kDa) was determined based on previous studies of biological effects of IGF-I on body and cartilage growth in mice (30). rhIGFBP-5 (29 kDa) was administered in an equimolar dose (50 µg/20 g mouse) to that of IGF-I. The mice were tail bled on days 7 and 14. On day 21 the mice were killed.
Exp 2. C3H/HeJ mice were divided into four groups of eight animals each. Group 1 received vehicle, group 2 received 13 µg/day IGF-I, group 3 received 50 µg/day rhIGFBP-5, and group 4 received 13 µg/day IGF-I and 50 µg/day of rhIGFBP-5. All groups received treatment for 9 days. On day 10 the mice were killed.
Exp 3. C3H/HeJ mice were divided into two groups of six animals each. These animals received only one injection (day 1); group 1 received vehicle, and group 2 received 50 µg/day rhIGFBP-5. On day 6 the mice were killed.
Exp 4. C3H/HeJ mice were divided into seven groups of six animals each. Groups 2–4 received 50 µg/mouse rhIGFBP-5, and groups 5–7 received 13 µg/mouse IGF-I. Group 1 was killed at time zero as the baseline group; groups 2 and 5 were killed at 1 h, groups 3 and 6 were killed at 6 h, and groups 4 and 7 were killed at 24 h post injection.
Serum collection. Whole blood was collected in 50-ml tubes and centrifuged at 3500 rpm in a cold IEC Centra-7R centrifuge (International Equipment Co., Needham, MA), and serum was skimmed off and stored at -70 C until assayed.
Femur collection. Both femurs were dissected out of each carcass and cleaned of soft tissue, being careful not to destroy the periosteum. Each bone was sectioned in the middiaphysis and rinsed in PBS at 4 C for 24 h, followed by extraction in 0.01% Triton X-100 at 4 C for 72 h. This bone extract was used for the ALP activity measurements.
Immunoblot. Serum from animals in Exp 4 was subjected to electrophoresis on a 12% acrylamide gel under denaturing conditions and transferred to a nitro-cellulose membrane, and the membrane was immunoblotted for rhIGFBP-5 using the same antibody as that used in the rhIGFBP-5 RIA, as described previously (31).
Gel filtration of treatment solution. To evaluate the extent of complex formation between IGF-I and rhIGFBP-5, an aliquot of the IGF-I/rhIGFBP-5 treatment solution used for these in vivo studies was subjected to size separation using Sephadex G-75. The proteins were eluted with PBS containing 0.1% BSA and 0.02% sodium azide, pH 7.2. The fractions were collected and assayed for IGF-I after separation of IGF-I from the IGFBPs by a biospin protocol (see below). Molecular mass standards were used to determine the elution positions of the 40-kDa (IGF-I/rhIGFBP-5 complex) and 7.7-kDa (IGF-I) proteins.
Biochemical assays
ALP activity assay. The ALP activity of the cell and bone
extract was determined as previously described (29).
Protein assay. The protein concentrations were determined using the Lowry Folin assay (28).
IGF-I RIA. Serum IGF-I was measured by specific RIA after separation from the IGFBPs. Because IGFBPs produce artifacts in IGF RIAs, it is essential to completely separate the IGFBPs from the IGFs for the IGF-I determinations to be valid, as previously described (32). The cross-reactivity of IGF-II in the IGF-I RIA is less than 0.5%. The sensitivity of the IGF-I RIA is less than 50 ng/liter; the intra- and interassay coefficients of variation are less than 10% (33). This assay was used to measure both endogenous mouse IGF-I and administered IGF-I.
rhIGFBP-5 RIA. Serum rhIGFBP-5 was measured by specific RIA using rhIGFBP-5 as standard and tracer as previously described (34). None of the other high affinity IGFBPs cross-react with the antiserum used in this assay. The sensitivity of the rhIGFBP-5 RIA is less than 5 ng/ml; the intra- and interassay coefficients of variation are less than 8%.
Osteocalcin assay. Human osteocalcin levels in conditioned medium and serum were measured by specific RIA (27). Mouse osteocalcin standard and tracer were purchased from BTI (Stoughton, MA). The mouse osteocalcin RIA had less than 8% interassay variability. We have previously developed and validated the mouse osteocalcin RIA (35).
Carboxyl-terminal cross-linked telopeptide of type I collagen (C-telopeptide) assay. C-telopeptide was measured in the mouse serum according to the manufacturer’s instructions using a Rat ICTP RIA Double Antibody Kit purchased from DiaSorin, Inc. (Stillwater, MN). The sensitivity of this assay is 0.5 µg/liter, and the mean recovery was 108.5%. The intra- and interassay coefficients of variation are less than 11% (36).
Statistics
Results are reported as the mean ± SEM for six
replicates for in vitro studies or six to eight animals per
group for in vivo studies and were compared by Student’s
t test, ANOVA, and Duncan’s post-hoc test as
appropriate. Results were considered significantly different for
P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). To
evaluate that the rhIGFBP-5-induced increase in osteocalcin level was
not due to increased cell number, osteocalcin levels were standardized
on the basis of cell protein to correct for changes in cell number.
rhIGFBP-5 (100 ng/ml) caused a significant increase in osteocalcin
levels even when the values were corrected for cellular protein
(0.2 ± 0.02 ng osteocalcin/µg cell protein in control
vs. 0.31 ± 0.06 ng osteocalcin/µg cell protein in
rhIGFBP-5-treated cells; P < 0.01). The specific
activity of ALP in cell extracts also showed a dose-dependent increase
with and without 10-8 M
1,25-(OH)2D3 (178 ± 18% and 169 ±
9% of control, respectively, at 100 ng/ml rhIGFBP-5; P
< 0.01; Fig. 2). Similar results were
obtained with normal human osteoblasts (data not shown).
1,25-(OH)2D3 has been shown to be essential for
the expression of osteocalcin in human osteoblasts and to increase ALP
activity (39). Based on the previous findings that rhIGFBP-5 increased
osteoblast cell proliferation (14, 20, 25) and the findings in this
study that rhIGFBP-5 increased the differentiative functions of
osteoblasts in vitro, we predicted that rhIGFBP-5 may
have a stimulatory effect on bone formation parameters in
vivo. We therefore tested the effect of rhIGFBP-5 on bone
formation parameters in vivo using a mouse model.
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Exp 1. Daily sc administration of rhIGFBP-5 (50 µg/day)
caused a significant increase in serum osteocalcin levels as early as
day 7 in BALB/c mice (Fig. 3); this
increase was maintained up to day 21. The magnitude of the
rhIGFBP-5-induced increase in osteocalcin was similar to that induced
by an equimolar dose of IGF-I.
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). As in the case of the BALB/c mice, in
C3H/HeJ mice the rhIGFBP-5-induced increase in serum osteocalcin was
similar to that which resulted from administration of an equimolar dose
of IGF-I (65%; P < 0.001; Fig. 4) and the combination
of IGF-I and rhIGFBP-5 (81%; P < 0.001; Fig. 4).
rhIGFBP-5 treatment caused a significantly greater increase in ALP
activity in femoral bone extract compared to an equimolar dose of
IGF-I or the combination of IGF-I and rhIGFBP-5 (Fig. 5). To determine whether rhIGFBP-5
modulates bone resorption as well as bone formation parameters, we
measured serum C telopeptide levels. These were significantly reduced
by 20% and 29% of the control value (P < 0.05),
respectively, in IGF-I- and rhIGFBP-5-treated animals (Fig. 6).
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).
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) after
rhIGFBP-5 injection; however, in the control IGF-I-treated animals,
serum IGF-I levels were increased by 111% of the baseline
(P < 0.01) at 1 h, indicating that the
administered IGF-I had reached the circulation. In addition, serum
rhIGFBP-5 levels were increased from 103 ± 24 ng/ml (at baseline)
to 353 ± 52 ng/ml 1 h after rhIGFBP-5 administration and had
returned to baseline value at 24 h (102 ± 40 ng/ml). To
determine whether the administered rhIGFBP-5 remains in an intact form,
pooled sera from baseline and rhIGFBP-5-treated groups (1 h after
treatment) were subjected to immunoblot analysis. Figure 9
shows that serum levels of both intact and fragment forms of rhIGFBP-5
were increased 1 h after rhIGFBP-5 administration.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Osteoblasts have been shown to produce all six of the high affinity IGFBPs known to date (4, 12, 16), although the amount of each IGFBP varies from cell line to cell line (41). There have been a number of in vitro studies that examined the effects of various IGFBPs on modulating the biological effects of IGF on various cell types, including osteoblasts (4, 12, 13, 16); however, there have been very few studies on the in vivo effects of IGFBPs, but those that exist are limited to IGFBP-3. In this regard, Bagi et al. (42, 43, 44) have shown that systemic administration of IGFBP-3 in combination with IGF-I increased bone formation in ovariectomized rats in a dose-dependent manner, with optimal effects at 7.5 mg/kg IGF-I complexed to an equimolar dose of IGFBP-3. In these studies, the complex of IGFBP-3/IGF-I produced consistently greater effects than IGF-I alone in stimulating bone formation. According to the researchers, this complex has a much longer half-life in the circulation and lowers blood glucose levels to a lesser extent than IGF-I alone because the IGF-I/IGFBP-3 binary complex binds to the circulating free acid-labile subunit (ALS) in the blood to form a 150-kDa complex that does not cross the vascular endothelium.
Surprisingly, in our study the combination of IGF-I and rhIGFBP-5 was less effective than rhIGFBP-5 alone in modulating changes in biochemical measurements of bone turnover in some, but not in other, experiments. The reason for this discrepancy is not clear at this time. One potential explanation is that, similar to IGFBP-3, rhIGFBP-5 when complexed to IGF-I has been shown to bind ALS (45). It is therefore possible that upon administration of IGF-I/rhIGFBP-5, some of this complex may exist in the 150-kDa complex by binding the ALS. This large molecular mass complex may trap the administered IGF-I as well as the rhIGFBP-5 in the serum, as the 150-kDa complex is too large to cross the vascular endothelium. Further studies are needed to test this possibility.
In contrast to the IGF-I/IGFBP-3 studies, our study shows that systemic administration of rhIGFBP-5 alone increased bone formation parameters in mice. rhIGFBP-5 treatment at the dose used in this experiment (50 µg/mouse) did not significantly alter the circulating levels of total IGF-I or the relative ratio of serum IGF-I in the 150- and 50-kDa forms (data not shown). Because rhIGFBP-5 has been shown to bind to ALS only when complexed to IGF-I and because only a small amount (<1%) of total IGF-I is present in the free form, it is possible that the majority of rhIGFBP-5 administered remains in a free form and is thus freely available to target tissues. We and others have reported indirect evidence showing that rhIGFBP-5 may affect osteoblasts by an IGF-independent mechanism (14, 40), raising the possibility that the bone-forming effects of rhIGFBP-5 may in part be mediated by an IGF-independent mechanism.
Although IGFBP-5 administration did not modulate circulating levels of IGF-I, we did not determine the effects of administered rhIGFBP-5 on local production of IGF-I or other IGF system components, which could provide a mechanism for the bone-forming effects of rhIGFBP-5. In addition, rhIGFBP-5 has been shown to bind to hydroxyapatite and extracellular matrix proteins and thereby may be involved in fixing locally produced IGFs in bone. Thus, it is possible that rhIGFBP-5 treatment may increase IGF-I content in bone and bring about the increases in bone formation parameters seen in this study. IGFBP-3 has also been shown to bind to certain extracellular matrix proteins, but not to hydroxyapatite (18, 46). Because the IGFBP-3 content in bone is much less than that of rhIGFBP-5 (18), this mechanism of action may not be as important in mediating IGFBP-3 effects to increase bone formation in the presence of IGF-I. Further studies are needed to establish that the mechanism by which rhIGFBP-5 mediates its bone-forming effects in vivo is different to that of IGFBP-3.
Our present study does not identify the target cells involved in mediating the bone-forming effects of rhIGFBP-5, as we indirectly evaluated bone formation by biochemical measurements of osteoblast cell activity and osteoblast cell products and not by direct histomorphometric methods. In this regard, the findings that serum osteocalcin and ALP activity in bone were increased by day 5 after a single injection of rhIGFBP-5 suggest that rhIGFBP-5 may affect existing osteoblastic cells. Further long term studies using histomorphometric techniques are needed to evaluate the target cells of rhIGFBP-5, as biochemical markers in serum and bone extracts are only indirect measurements of osteoblast cell number and activity.
In contrast to the effects on bone formation parameters, short term administration of both rhIGFBP-5 and IGF-I decreased serum C-telopeptide levels, a marker of bone resorption. In contrast to these effects in mice, short term administration of IGF-I has been shown to increase bone resorption markers in elderly postmenopausal women (47). There are a number of potential explanations for the observed differences between IGF-I effects in mice and humans. IGF-I may have different effects in mice than in humans, Jonsson et al. (48) showed that IGF-I had no effect on 45Ca release from prelabeled neonatal mouse calvarial bones, although IGF-I pretreatment increased the formation of multinucleate tartrate-resistant acid phosphate-positive cells in murine bone marrow cultures. In addition, IGF-I treatment inhibited bone resorption-induced by PGE2 and 1,25-(OH)2D3 (48). Alternatively, the IGF-I effects on bone resorption may be different depending on estrogen status. The mice used in these studies were intact young animals (7 weeks old) as opposed to the human IGF-I studies that were performed in postmenopausal women. Further studies are needed to evaluate whether IGF-I also decreases bone resorption in estrogen-deficient (ovariectomized) older mice and, if so, what is the molecular basis for the observed differences in IGF-I effects on bone resorption between mice and humans.
In conclusion, this study demonstrates for the first time that a single administration of rhIGFBP-5 increases bone formation parameters; however, this increase in bone formation parameters is not mediated by increases in serum IGF-I levels. We also show that rhIGFBP-5 administration decreases bone resorption parameters in mice. We have shown that rhIGFBP-5 is as potent as IGF-I in stimulating bone formation parameters. Long term studies on the effects of rhIGFBP-5 on bone histomorphometry, bone density, and bone strength are essential to confirm the anabolic effects of rhIGFBP-5 on bone.
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Acknowledgments |
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Footnotes |
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Received February 22, 1999.
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