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Section of Endocrinology (A.G., M.-A.M., U.M., B.-H.S., K.I.), Yale University School of Medicine, New Haven, Connecticut 06520-8020; Laboratory of Genetics (S.R.), National Cancer Institute, Bethesda, Maryland 20892; University of Arkansas for Medical Sciences (R.J., S.M.), Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Dr. Karl Insogna, Section of Endocrinology, Yale University School of Medicine, P.O. Box 208020, 333 Cedar Street, New Haven, Connecticut 06520-8020. E-mail: karl.insogna{at}yale.edu
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism(s) by which PTH regulates bone resorption at a cellular level are not fully understood. However, the stimulatory effect of PTH on the development and activity of the bone-resorbing cell, the osteoclast, requires the presence of stromal/osteoblastic cells (7), suggesting that PTH induces cells of the osteoblast lineage to produce factor(s) that recruit and/or activate osteoclasts. Among the factors produced by stromal/osteoblastic cells in response to PTH are colony-stimulating factor-1 (8), interleukin-11 (9, 10), osteoclast differentiation factor/TRANCE/RANKL (11, 12), and interleukin-6 (IL-6) (13, 14, 15, 16, 17, 18, 19, 20). Whether any of these agents mediate the effects of PTH on osteoclasts is not known, but a growing body of evidence suggests that IL-6 may do so. IL-6 potently promotes osteoclastogenesis (21) and is thought to play a role in the bone loss which accompanies sex steroid deficiency (22, 23). In vitro studies have demonstrated that IL-6 is produced by stromal/osteoblastic cells in response to PTH (13, 14, 15, 16, 17, 18, 19, 20), and that PTH-induced bone resorption by osteoclast-like cells is inhibited by an antibody to the IL-6 receptor (24).
Few in vivo data are available that examine the regulation of IL-6 by PTH, or the role of IL-6 in PTH-induced bone resorption. Local in vivo administration of PTH increases IL-6 expression in murine calvariae (25). We recently reported that in patients with primary hyperparathyroidism, a disease characterized by chronic PTH excess, circulating levels of IL-6 are elevated and correlate strongly with biochemical markers of bone resorption (26). In the current studies, we have used animal models to further characterize the relationships among PTH, IL-6 and bone resorption in vivo. The findings demonstrate that circulating levels of IL-6 are regulated by PTH, that IL-6 is important for PTH-induced bone resorption, and that IL-6 may participate in coupling PTH-induced bone resorption to formation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice in which the IL-6 gene had been disrupted by homologous recombination (27) were generously provided by Dr. Manfred Kopf. The IL-6 null allele was back-crossed onto a BALB/cAN background for four generations before use in the current experiments.
Validation of bone resorption markers
Six-week old Swiss-Webster mice were either sham-operated (Shm)
or ovariectomized (Ovx). Two weeks after Ovx, animals were assigned to
no treatment, 17ß-estradiol or its vehicle for 2 weeks. At the end of
the two-week treatment period, blood and urine samples were obtained by
cardiac puncture and abdominal compression respectively, and assayed
for markers of bone resorption. Five animals were studied under each
experimental condition.
To assess the effect of specific inhibition of osteoclastic bone resorption on PTH-induced changes in the biochemical markers of bone resorption, CD-1 mice were administered the bisphosphonate pamidronate, 0.15 mg/kg in 0.9% NaCl, or vehicle, by sc injection on days -3, 0, and +3 of a 5-day infusion of human PTH (1–84) (n = 5) or vehicle (n = 5), performed as described below. Serum and urine samples were collected at the conclusion of the infusion.
PTH infusions
PTH infusions in CD-1 mice, Sprague Dawley rats, and IL-6
knockout mice and their wild-type littermates were performed according
to the following protocol. Human PTH (1–84) or (51–84) was
reconstituted in 2% L-cysteine, pH 1.5, and loaded into
Alzet osmotic minipumps, which deliver 0.5 µl/h. The pumps were
equilibrated in 0.9% NaCl overnight at 37 C and then implanted into an
interscapular sc pocket under Metaphane anesthesia. Mice were infused
at a rate of 4.3 pmol/h for 5 days, at which time serum and urine
samples were obtained by cardiac puncture and abdominal compression
respectively. Rats were infused at a rate of 12.9 pmol/h for 5 days,
during which time serum and urine samples were collected daily, by tail
bleed and abdominal compression respectively. Animals perfused with
vehicle, which were studied in a parallel fashion using an identical
protocol, received 2% L-cysteine only. Serum and urine
samples were stored at -20 C until analyzed.
In IL-6 neutralization experiments, adult female CD-1 mice received an
ip injection of 1 mg of either a monoclonal neutralizing antibody to
IL-6 (28), or an isotype-matched antibody (clone RR8–1, to the V
11.1 and V 11.2 murine T cell receptors, which are not expressed in
CD-1 mice), immediately before initiation of the PTH infusion. PTH
infusion and sample collection were then carried out as outlined above.
The control antibody was kindly provided by Dr. Kim Bottomly (Yale
University Hybridoma Center).
Measurement of cytokines and markers of bone turnover
Serum IL-6 was measured using a murine solid-phase enzyme-linked
immunosorbent assay (R&D Systems, Minneapolis, MN). Antibody incubation
times were adjusted to increase the sensitivity of the assay, which in
our laboratory is 3.9 pg/ml. The intraassay and interassay coefficients
of variation (CV) for this assay in our laboratory are 3.2% and 4.1%
respectively.
Serum rat type I collagen carboxyterminal telopeptide (ICTP) was measured by an equilibrium RIA (INCSTAR Corp., Stillwater, MN), with a sensitivity of 0.5 µg/liter. The intraassay and interassay CVs are 2.8% and 3.6% respectively.
The level of urinary carboxyterminal telopeptides of type I collagen (hereafter referred to as urine collagen cross-links) was measured using an enzyme-linked immunosorbent assay and a rat collagen cross-links standard (CrossLaps, Diagnostics Systems Laboratories, Inc. Webster, TX). The results were corrected for urinary creatinine, which was measured by a colorimetric method using alkaline picrate solution. Assay conditions were modified by adjusting antibody incubation times to achieve a sensitivity of 25 µg/mmol creatinine. The intraassay and interassay CVs are 3.8% and 4.9% respectively.
Serum osteocalcin was measured using a murine immunoradiometric assay (Immunotopics International, San Clemente, CA), with a sensitivity of 2.5 ng/ml. The intraassay and interassay CVs in our laboratory are 2.6% and 3.6%, respectively.
Urinary deoxypyridinoline was measured using a human competitive enzyme immunoassay (Metra Biosystems, Mountain View, CA), which cross-reacts with rodent deoxypyridinoline (29, 30). The intraassay and interassay CVs in our laboratory are 3.6% and 4.4%, respectively. Serum calcium was measured using a model 2380 atomic absorptiometer (Perkin-Elmer Corp., Norwalk, CT). Circulating levels of human PTH were measured using an intact PTH immunoradiometric assay (coated tube and coated bead assay) (Diagnostics Systems Laboratories, Inc. Webster, TX). The assay has a sensitivity of 1 pg/ml. In our laboratory, intrassay and interasssay CVs were 2.9% and 3.9%, respectively.
Statistical analyses
Statistical analyses were performed using the statistical
packages Oxstat (Medstat Ltd, Nottingham, UK) and SAS, version 6.12
(SAS Institute, Inc., Cary, NC). Between-group comparisons
were made using the Students t test for unpaired samples,
and ANOVA. Data from the experiments in rats were analyzed by
repeated-measures ANOVA. Bivariate correlations between biochemical
variables were performed using Pearson’s r. All data are mean ±
SD, unless otherwise specified.
The study was approved by the Yale Animal Care and Use Committee.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Thus, the mean (± SD)
level of serum ICTP was 9.5 ± 1.1 µg/liter in ovariectomized
mice (Ovx), and 4.3 ± 0.7 µg/liter in Shm (P <
0.01), and that of urinary collagen cross-links was 65 ± 9
µg/mmol creatinine in Ovx, and 29 ± 7 µg/mmol creatinine in
Shm (P < 0.01). For each marker, 17ß-estradiol fully
reversed the effect of Ovx, whereas placebo therapy had no effect (Fig. 1a).
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). Thus, mean (±
SD) levels of urine collagen cross-links and serum ICTP in
mice pretreated with vehicle and infused with PTH were 70 ± 9
µg/mmol creatinine and 10.6 ± 1.4 µg/liter, respectively.
Mice pretreated with pamidronate and infused with PTH had mean (±
SD) levels of urine collagen cross-links and serum ICTP of
29 ± 4 µg/mmol creatinine and 3.0 ± 0.6 µg/liter,
respectively (P < 0.0001 vs. vehicle
pretreatment for each marker). These data demonstrate that the
biochemical markers used in this study specifically measure bone
resorption. Urine deoxypyridinoline, which has previously been shown to reflect bone resorption in rodents (29, 30), and urinary collagen cross-links were measured in CD-1 mice exposed to a variety of experimental conditions (basal, PTH infusion, Ovx, Ovx + PTH infusion, n = 5 for each). There was a strong positive association between the two bone resorption markers (r = 0.98, P < 0.001), further confirming the validity of the resorption markers we used.
PTH infusion in normal rodents
Human PTH (1–84) infusion in CD-1 mice induced a substantial
increase in levels of circulating PTH, with mean levels at the
conclusion of the 5-day infusion being 305 pg/ml in hPTH
(1–84)-treated animals, and 5 pg/ml in vehicle-treated animals.
PTH (1–84) infusion increased levels of serum IL-6 and each of the
bone resorption markers in normal mice (Fig. 2). At the conclusion of the 5-day study
period, the mean (± SD) level of serum IL-6 in the PTH
(1–84)-treated animals was 7 times higher than in the control group
(PTH (1–84)-treated 17.9 ± 6.5 pg/ml, vehicle-treated 2.7
± 0.7; P = 0.002) (Fig. 2a). In the PTH
(1–84)-treated group, the mean level of each of the markers of bone
resorption was increased approximately 3-fold over control values
(urinary collagen cross-links—PTH (1–84)-treated: 169 ± 117
µg/mmol creatinine; vehicle-treated: 41 ± 4, P
< 0.01; ICTP—PTH (1–84)-treated: 12.8 ± 1.6 µg/liter,
vehicle-treated: 4.6 ± 0.7, P < 0.0001) (Fig. 2, b and c, respectively). In the PTH (1–84)-treated animals, levels of
IL-6 were highly positively correlated with those of both urinary
collagen cross-links (r = 0.95, P < 0.01) and
ICTP (r = 0.99, P < 0.001). Infusion of PTH
(51–84) induced a small increase in serum IL-6 levels (mean
± SD 5.7 ± 0.6 pg/ml vs. 2.7 ± 0.7
in vehicle-treated animals, P < 0.01), but did not
alter levels of either bone resorption marker.
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In normal rats, PTH infusion also increased the levels of IL-6 and each
of the markers of bone resorption (Fig. 3). In the vehicle-treated animals,
levels of serum IL-6, serum ICTP and urinary collagen cross-links were
unchanged during the infusion. The mean level of each of these
variables was significantly greater in the PTH-treated group than the
control group during the study period (P < 0.005 for
each). Serum calcium did not change in response to PTH infusion
(mean ± SEM change from baseline, PTH-treated
-0.3 ± 0.2 mg/dl, vehicle-treated -0.3 ± 0.1,
P = 1.0). Levels of serum IL-6 at the end of the
infusion were strongly positively correlated with those of each of the
bone resorption markers in the PTH-treated animals (ICTP, r =
0.92, P < 0.05; urinary collagen cross-links, r =
0.79, P = 0.1).
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). Thus, the mean (± SD)
urine collagen cross-links level after 5 days of PTH infusion in the
mice pretreated with IL-6 antibody was 14.3 ± 4.0 µg/mmol
creatinine, whereas that in the mice pretreated with control antibody
was 50.4 ± 8.7 (P < 0.001) (Fig. 4a). The mean
(± SD) ICTP level in the mice pretreated with antibody to
IL-6 was 5.0 ± 1.2 µg/liter, whereas that in the mice
pretreated with the control antibody was 9.4 ± 1.1
(P < 0.001) (Fig. 4b). Neutralization of IL-6 did not,
however, affect PTH-induced increases in serum osteocalcin (Fig. 4c).
Mean (± SD) levels of this marker of differentiated
osteoblast function after 5 days of PTH infusion were 166 ± 19
ng/ml in mice treated with the antibody to IL-6 and 172 ± 21
ng/ml in those treated with the control antibody (p = NS).
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. At baseline, the mean (±
SD) level of each resorption marker was significantly lower
in the IL-6-/- mice than IL-6+/+ animals
(urinary collagen cross-links—IL-6-/-: 17.3 ± 3.3
µg/mmol creatinine; IL-6+/+: 32.4 ± 4.0,
P < 0.0001; ICTP—IL-6-/-: 3.1 ±
0.4 µg/liter, IL-6+/+: 4.5 ± 0.7, P
< 0.0001) (Fig. 5, a and b, respectively). In contrast, the baseline
serum osteocalcin level in the IL-6-/- mice (100 ±
12 ng/ml) was significantly higher than that in the IL-6+/+
animals (74 ± 9 ng/ml, P = 0.005) (Fig. 5c). In
the IL-6+/+ mice, the PTH-induced increase in the level of
each resorption marker was considerably greater than that in
IL-6-/- animals (mean ± SEM increase
from baseline, urinary collagen cross-links—IL-6+/+:
36.8 ± 3.1 µg/mmol creatinine, IL-6-/- 2.6
± 1.4, P < 0.0001; ICTP—IL-6+/+:
2.6 ± 0.3 µg/liter, IL-6-/-: 0.5 ± 0.2,
P < 0.0001). In the IL-6-/- mice, levels
of urinary collagen cross-links and ICTP after PTH infusion were 15%
and 16% higher, respectively, than those in untreated knockout
animals, whereas in the IL-6+/+ animals, the corresponding
increases were 114% and 58%. Osteocalcin levels in the
IL-6+/+ animals following PTH infusion (112 ± 15
ng/ml) were significantly higher than baseline values (74 ± 11
ng/ml, P < 0.001), but did not change in the
IL-6-/- mice (PTH-treated 95 ± 14 ng/ml; baseline
100 ± 12 ng/ml, p = NS).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The findings for markers of bone resorption in the IL-6 knockout animals are consistent with the observations made in the antibody neutralizing experiments. However, a detailed assessment of mineral homeostasis in these animals has not been reported, so other explanations are possible. Thus, we have recently observed that IL-6 knockout animals have secondary hyperparathyroidism (Mitnick, M., unpublished observation) and this may affect the response to exogenously administered PTH. In particular, this may explain the discrepancy between the response of serum osteocalcin to PTH infusion in the settings of acute IL-6 neutralization, in which it increases normally, and chronic IL-6 deficiency, in which osteocalcin levels are elevated basally, probably in response to increased endogenous PTH levels, and do not change upon exogenous PTH administration. The bone turnover data from the IL-6 neutralization experiments, in which endogenous PTH levels were similar in the treatment groups, suggest that IL-6 plays a role in coupling PTH-induced bone resorption and formation.
As indices of bone resorption, we used the serum and urine concentrations of the carboxyterminal telopeptide of type I collagen. The assessment of bone resorption using biochemical markers specific for bone catabolism is commonly undertaken in human studies (31) but has not to date been widely applied to animal studies. We validated the assays for the bone resorption markers used in the current study by showing (a) that the mean level of each increased substantially in mice in response to estrogen withdrawal, a known stimulus of bone resorption (32), and was normalized by estrogen replacement, (b) that the bisphosphonate pamidronate, a specific inhibitor of osteoclastic bone resorption, blocked the PTH-induced increase in each of the resorption markers, and (c) that there was a strong positive correlation between levels of urine collagen cross-links and those of urinary deoxypyridinoline, a validated marker of bone resorption in rodents (29, 30). The finding that the mean level of each of the bone resorption markers in the wild-type littermates of the IL-6 knockout mice was lower than that in the CD-1 mice following PTH infusion may reflect a difference in sensitivity to PTH between the two strains of mice. Thus, the increase in serum IL-6 (mean ± SEM) in response to PTH was also smaller in the wild-type littermates of the IL-6 knockout mice (8.0 ± 0.7 pg/ml) than in CD-1 animals (16.1 ± 2.9 pg/ml).
Most hormonal agents that influence bone resorption, including PTH, are thought to do so indirectly, by acting upon stromal/osteoblastic cells to stimulate the production of either soluble or membrane-bound factors that regulate osteoclast number and function (33). Among the factors produced by stromal/osteoblastic cells in response to PTH are colony-stimulating factor-1 (8), interleukin-11 (9, 10), osteoclast differentiation factor/TRANCE/RANKL (11, 12), and IL-6 (13, 14, 15, 16, 17, 18, 19, 20). Although evidence exists from in vitro studies for a role for several of these cytokines in the bone-resorbing actions of PTH (8, 24), the current study is the first, to our knowledge, to examine the role of a cytokine in PTH-induced bone resorption in vivo. Our data complement and extend those from several in vitro studies, which have demonstrated PTH-induced IL-6 production by osteoblastic and stromal cells (13, 14, 15, 16, 17, 18, 19, 20), and inhibition of PTH-induced bone resorption by an antibody to the IL-6 receptor (24). We have now found highly positive correlations between levels of serum IL-6 and those of bone resorption markers in humans exposed to chronic PTH excess (26) and rodents subjected to short-term PTH infusion (current study), consistent with the hypothesis that IL-6 plays a role in mediating the bone-resorbing actions of PTH in vivo. The current study provides direct evidence to support this notion.
Our data do not, however, exclude the possibility that factors other
than IL-6 may contribute to PTH-induced bone resorption because PTH
infusion in the IL-6 knockout animals induced small but consistent
increases in each of the resorption markers. In vitro, the
inhibition of PTH-stimulated bone resorption by an antibody to the IL-6
receptor can be overcome by increasing the concentration of PTH (24),
further suggesting the existence of non-IL-6 mediated pathways of
PTH-induced bone resorption. It is therefore possible that a higher
dose of PTH than that used in the current study might in part overcome
the inhibitory effects on bone resorption of neutralizing antiserum to
IL-6, or induce greater bone resorption in the IL-6 knockout animals.
Because the dose of PTH we used did not induce hypercalcemia, the role
of IL-6 in PTH-induced hypercalcemia remains to be determined. In
vivo, the serum levels of both tumor necrosis factor- and the
IL-6 soluble receptor are increased in response to PTH (26). Either or
both of these cytokines may contribute to PTH-induced bone resorption
because tumor necrosis factor- is known to stimulate production by
osteoblastic cells of IL-6 (34, 35), and the IL-6 soluble receptor acts
synergistically with its ligand to stimulate osteoclastic bone
resorption (36).
The tissue source(s) of the circulating IL-6 produced in response to PTH remains uncertain. Because bone cells produce IL-6 in response to PTH, the skeleton probably contributes to this phenomenon. However, because type 1 PTH receptors are expressed in a variety of tissues (37), and IL-6 is produced by a variety of cell types, there may be other tissue sources contributing to the increased level of circulating IL-6 we observed. Thus, we have recently observed PTH-induced IL-6 production in the isolated perfused rat liver (38). This finding may explain the small increase in circulating IL-6 we found in mice infused with PTH (51–84) because the PTH (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) fragment induced significant IL-6 production by the liver ex vivo, suggesting that truncated forms of the hormone may be biologically active in that organ. A reduction in clearance of IL-6 following PTH administration may also contribute to the elevated serum IL-6 levels, as PTH increases the serum level of the IL-6 soluble receptor (26), which in turn prolongs the plasma half-life of IL-6 (39).
The biological significance with regard to bone resorption of the PTH-induced rise in circulating as opposed to skeletal IL-6 is uncertain. It is not clear whether it merely reflects "spillover" of excess local production of the cytokine in tissues such as bone, or represents bioactive cytokine functioning as a hormone, with bone as a target tissue. However, recent evidence implicates IL-6 as an endocrine agent in the regulation of the hypothalamic-pituitary-adrenal axis (40). Our data therefore raise the possibility that the actions of PTH on bone resorption may in part be mediated by IL-6 produced at sites other than the skeleton.
IL-6 has previously been implicated in the increased bone resorption, and bone loss, that accompanies sex steroid deficiency (9, 10). Our data (26, current study) suggest that it may also contribute to the disregulation of skeletal homeostasis and bone loss that accompanies altered circulating levels of a second major osteotropic hormone, PTH. Targeted inhibition or neutralization of IL-6 may therefore represent an effective therapeutic strategy for the management of these common forms of osteoporosis.
In summary, our study demonstrates in a prospective fashion that short-term PTH infusion induces a rapid and substantial increase in the level of circulating IL-6 in experimental animals. This occurs coincidentally with an increase in biochemical markers of bone resorption. The absence or neutralization of IL-6 is accompanied by abrogation of the PTH-induced increase in markers of bone resorption, suggesting that IL-6 plays a key role in the bone-resorbing effects of PTH in vivo. Neutralization of IL-6 does not affect the response of bone formation markers to PTH, suggesting a role for IL-6 in coupling PTH-induced bone resorption and formation.
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Acknowledgments |
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Footnotes |
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Received December 3, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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are elevated in primary hyperparathyroidism, and
correlate with markers of bone resorption. J Clin Endocrinol Metab 81:3450–3454[Abstract]
is not regulated by ovarian
steroids. Endocrinology 136:4056–4067[Abstract]
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A. A. Ragab, J. L. Nalepka, Y. Bi, and E. M. Greenfield Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells Am J Physiol Cell Physiol, September 1, 2002; 283(3): C679 - C687. [Abstract] [Full Text] [PDF]
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U. S. Masiukiewicz, M. Mitnick, B. I. Gulanski, and K. L. In |
, n = 5), or vehicle (
, n = 5), via sc placed
osmotic minipumps for 5 days. Serum and urine samples collected at
daily intervals during the infusion were assayed for (a) serum IL-6,
(b) urine collagen cross-links, and (c) serum type I collagen
carboxyterminal telopeptide (ICTP). The horizontal bars
represent the SEM.
6), and their wild-type
littermates (IL-6+/+, n