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Division of Endocrinology, University of Pittsburgh Medical Center (B.B.), Pittsburgh, Pennsylvania 15261; Divisions of Gastroenterology (L.C.H.) and Endocrinology, Zentrum fuer Innere Medizin, Philipps University, Marburg D-35033, Germany; Endocrine Research Unit (T.T., F.G., S.K., L.R.) and Department of Orthopedics (G.L.E., R.T.T.), Mayo Clinic, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Barto Burguera, M.D., Ph.D., Division of Endocrinology, E-1140 BST, University of Pittsburgh Medical Center. Pittsburgh, Pennsylvania 15261. E-mail: burguerab{at}msx.dept-med.pitt.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because leptin is almost entirely produced by white adipose tissue, serum leptin levels are increased in obesity and are strongly and directly related to fat mass (11). Leptin circulates in plasma and, after crossing the blood-brain barrier, acts in the hypothalamic nuclei to regulate food intake, energy expenditure, growth, and sexual maturation (12). In addition to its effects in the central nervous system (13, 14), recent studies have shown that leptin also acts in the periphery, where leptin receptors have been described (12). Leptin has the capability of suppressing specific biochemical reactions that contribute to lipid accumulation and adipocyte differentiation (15), as well as modulating T cell immune responses and reversing the immunosuppressive effects of acute starvation (16). Using a conditionally immortalized human marrow stromal (hMS) cell line with the potential to differentiate to either osteoblastic or adipocytic lineages (17, 18), we have recently demonstrated that stromal cells produce functional leptin receptors. Furthermore, leptin exerted direct osteogenic effects in vitro by enhancing osteoblastic differentiation and inhibiting late adipocytic differentiation of the hMS cells (18). The hMS cell line also expresses the two key osteoclast determinants, RANK ligand (RANKL) and OPG (18, 19). RANKL is a novel member of the TNF ligand superfamily that is essential for osteoclast differentiation and activation (20). The stimulatory effects of RANKL in the bone microenvironment are neutralized by the secreted decoy receptor OPG (21). The balance between OPG and RANKL secretion by stromal cells is critical to the regulation of osteoclast formation. For example, factors known to induce osteoclast formation may increase both OPG and RANKL levels, with the increase in RANKL exceeding that in OPG (22).
The in vivo effects of leptin on bone metabolism are controversial. Ducy et al. (23) have recently shown that leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice have increased bone mass despite hypogonadism and hypercortisolism. On the contrary, Steppan et al. (24) showed that leptin administration led to a significant increase in femoral length, total body bone area, bone mineral content, and bone density in ob/ob mice compared with those in vehicle-treated controls.
To further evaluate whether leptin could be a hormonal mediator
relating fat and bone mass, we explored the effects of leptin on bone
metabolism in vivo. The effect of leptin on bone mass was
studied for 1 month in ovariectomized (OVX) Sprague Dawley rats and was
compared with that of 17
-ethinyl estradiol (E2) and a combination of
leptin and E2.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sprague Dawley rats were obtained from Charles River Laboratories, Inc. (Portage, MI), at 6 months of age and body weight of 283 ± 5.1 g (mean ± SEM). Bilateral ovariectomy (n = 56; OVX) or sham surgery (n = 8; intact) was performed at 5 months and 3 wk of age. At 4 d postsurgery, OVX rats were stratified by weight and randomized to a baseline (n = 8) or one of the five groups (n = 8 rats/group): 1) leptin; 2) E2; 3) leptin plus E2; 4) vehicle; and 5) and a group pair fed to the leptin-treated group. Treatment was not started until 7 d post-OVX to allow for the estrogen levels to become completely depleted. A continuous sc administration of leptin (100 µg/day) was performed using Alzet osmotic pumps (ALZET, Cupertino, CA). This dose was selected from the literature, based on its potential to effectively modulate food intake without impairing growth (25, 26, 27). We used recombinant human leptin provided by Eli Lilly & Co. (Indianapolis, IN), according to previous studies that showed the effectiveness of human leptin in rodents (28, 29). E2 was administered sc at a concentration of 200 µg/kg·d, using slow release tablets. Fluorochromes to label mineralizing bone surfaces were administered by juxta-tail vein injection 1 d before starting treatment (calcein-tetracycline-HCl, 20 mg/kg BW; Sigma, St. Louis, MO), 10 d before death (tetracycline, 20 mg/kg BW; Sigma), and 3 d before death (calcein as described). The two fluorochrome labels are readily differentiated under UV illumination, with tetracycline fluorescing in pale yellow and calcein fluorescing in bright green.
Bone histomorphometry
Histomorphometric measurements were made with the osteomeasure
semiautomatic analysis system (Osteomeasure Instruments, Inc., Atlanta,
GA) as previously described (30). The regions of interest
were traced, and the line lengths and defined areas were calculated by
computer.
Cortical bone measurements. Ground transverse sections were used for histomorphometric analysis of cortical bone. Cross-sections of 150 µm were cut at a site just proximal to the tibia-fibula synostosis with a low speed saw (Isomet, Buehler, Lake Bluff, IL) equipped with a diamond wafer blade. The sections were ground to a thickness of 15–20 µm on a roughened glass plate and mounted in glycerol before microscopic examination under UV illumination to visualize fluorochrome labeling. The following parameters were determined as previously described (30): cross-sectional area, defined as the area of bone and marrow cavity bounded by the periosteal surface of the specimen; medullary area, defined as the area delineated by the endocortical surface of the specimen; cortical bone area, calculated as the difference between the cross-sectional and the medullary area; periosteal perimeter, defined as the total perimeter enclosing the cross-section (periosteal perimeter includes fluorochrome-labeled and nonlabeled perimeters); periosteal bone formation rate, calculated as the area bounded by tetracycline labels divided by the labeling period of 26 d; and periosteal mineral apposition rate (MAR), defined as the periosteal bone formation rate divided by the labeled perimeter. These measurements have been described previously (30) and follow the standard nomenclature recommended by Parfitt et al. (31).
Cancellous bone histomorphometry. After fixation for a minimum of 2 d in 70% ethanol, the proximal tibial metaphyses were dehydrated in a series of increasing concentrations of ethanol and embedded without demineralization in a mixture of methylmethacrylate-2-hydroxyethyl-methacrylate. The embedded tibiae were sectioned at an indicated thickness of 5 µm on the Reichert-Jung Supercut 2050 microtome to obtain midcoronal sections. Bone measurements were performed in toluidine blue-stained sections. The sampling site used was 1 mm distal to the growth plate in the secondary spongiosa and extended bilaterally in each section excluding the endocortical surfaces.
Bone formation measurements and calculations. The bone formation rate was calculated as the product of the double labeled surfaces and the MAR. The MAR, expressed as microns per d, was the mean distance between the tetracycline and calcein labels divided by the labeling interval of 10 d. Double labeled surfaces were determined as the bone surfaces with both tetracycline and calcein labels.
Dynamic measurement related to bone resorption. Calcein label perimeters were measured in a growth-adjusted metaphyseal sampling site, and subsequent resorption was calculated as previously described by Westerlind et al. (30).
Northern analysis
Total RNA was isolated from conditionally immortalized hMS cells
(17) cultured in the presence of 10% FCS using the
QIAGEN RNeasy kit in combination with the QiaShredder
(QIAGEN, Hilden, Germany). These cells are authentic
osteoblastic precursors and are capable of differentiating into
osteoblasts or adipocytes with a complete mature phenotype depending on
the culture conditions as previously described (17). Ten
micrograms of total RNA were separated on a 1.5% (wt/vol) agarose gel
containing formaldehyde (2.2 M) using continuous buffer
circulation and then transferred to a nylon membrane (Hybond N+,
Amersham Pharmacia Biotech, Arlington Heights, IL) by
capillary blotting (19). The human cDNA inserts, a
ß-actin cDNA that hybridized to a 2.0-kb mRNA, a full-length OPG cDNA
(GenBank accession no. U94332) that hybridized to a 2.9-kb mRNA, and a
RANKL cDNA (GenBank accession no. AB036798) that hybridized to a mRNA
species of 2.4 kb were radiolabeled by random primer labeling. Band
intensity was quantified by densitometry. Control hybridization with
human ß-actin verified that equal amounts of RNA were loaded. All
experiments were carried out at least three times, and representative
blots are shown.
OPG protein assay
The primary marrow stromal cells (MSC) were plated at a density
of 5000 cells/cm2, grown for 7 d in basal
proliferation medium containing 10% charcoal-stripped FCS, and treated
for up to 21 d in at 37 C in osteogenesis induction medium
containing 10% charcoal-stripped FCS, 0.1 µM
dexamethasone, 0.05 mM ascorbic acid-2-phosphate, and 10
mM ß-glycerol phosphate as previously described
(32). At the time of cell harvest, the MSC covered more
than 90% of the petri dishes, and more than 90% of cells were viable.
MSC were treated with freshly prepared leptin at 100 or 1000 ng/ml
(resuspended in phosphate buffer disodium, 120 µM, pH
7.5) or vehicle for 0, 3, 7, or 21 d. The medium (PT-3001,
BioWhittaker, Inc., Walkersville, MD) was changed twice
per week, and the leptin treatment was repeated at the time of the
medium change. The conditioned medium (n = 9 or n = 6) was
centrifuged at 1000 rpm to remove cell debris and stored at -80 C
until analysis. OPG protein was measured using the OPG ELISA system
from Immundiagnostik (Bensheim, Germany) according to the
manufacturer’s instructions. The protein data were normalized to the
total RNA content as a surrogate of the cell number.
Statistical analysis
ANOVA was performed with post-hoc Newman-Keuls
multiple comparison testing. P < 0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the effect of sc
leptin therapy vs. E2, leptin plus E2, and sham treatment on
body weight in rats over 28 d. The expected OVX-induced weight
gain was prevented by the administration of estrogen. The
leptin-treated, vehicle-treated, and pair-fed groups gained a
statistically significant amount of body weight compared with the
sham-operated, E2-treated, or E2- plus leptin-treated groups. On the
other hand, the leptin-treated group had a significantly lower body
weight at the end of the study compared with the vehicle-treated group
(P < 0.05), but it was not significantly different
from that of the pair-fed group. Thus, the dose and route of
administration we used for leptin treatment were partially effective in
modulating appetite and limiting weight gain. However, the rate of body
weight gain in the leptin-treated group was intermediate between the
vehicle and the E2-treated groups, therefore avoiding any bias due to
starvation on bone metabolism. Food intake in the leptin-treated group
was not statistically significantly different from that in the
vehicle-treated group (Fig. 2). Food
intake in the leptin plus E2 group was significantly lower compared
with those in the vehicle and sham group during the first 10 d of
the study; however, these differences resolved with time. The leptin
and leptin plus E2 groups had significantly higher levels of plasma
leptin than the control (P < 0.05), but levels
remained within the physiological range (Table 1). Levels of leptin in the cerebrospinal
fluid were not statistically significant different between the groups
(Table 1).
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) as well as the combination of leptin
and E2. Leptin treatment alone was also effective in attenuating the
decrease in BV/TV (69% higher than vehicle) and had a
protective effect on trabecular bone architecture, with preservation of
trabeculae number (Fig. 4). Trabecular
thickness in the leptin-treated group was not significantly different
from that in the vehicle-treated group (data not shown).
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). These data suggest that leptin
effects on OVX-induced trabecular bone loss could be mediated by
impairing osteoclast activity, rather than by altering osteoclast
number or bone formation.
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). As in cancellous bone, the
combination of E2 and leptin further decreased cortical BFR compared
with values in estrogen-treated OVX and sham rats. This effect was due
to a decrease in MAR.
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). To confirm OPG regulation by leptin
in normal nontransformed primary MSC, we employed the MSC assay.
OPG secretion by MSC increased 6-fold over the course of 21 d
(P < 0.001, by ANOVA), and leptin dose-dependently
enhanced OPG protein secretion (by 15–31% at a concentration of 1
mg/ml) at each of the three time points (P < 0.005
after 3 d, by ANOVA; P < 0.01 after 7 and 21
d, respectively, by ANOVA; Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Obesity appears to have a protective effect on osteoporosis in humans and inversely correlates with the risk of bone fractures (33, 34). Even though the effects of estrogen and body weight-bearing are partially responsible for these actions, other factors closely related to body fat may have a crucial effect on the increased bone density characteristic of obese humans. Ozata et al. (35) have recently shown that four patients with human leptin deficiency caused by a missense mutation had alterations in PTH and calcium metabolism, and one of these patients had a marked decrease in BMD, which it is in contrast to nonleptin-deficient obese individuals, who are protected against osteoporosis. Farooqi et al. (36) also reported that 1 yr of leptin therapy in a child with congenital leptin deficiency induced a decrease in body fat by 15.6 kg and a decrease in lean mass by 0.82 kg, but increased bone mineral mass by 0.15 kg. Thomas et al. (37) recently reported that serum leptin levels were directly related to BMD in women in both weight-bearing and nonweight-bearing sites, suggesting that leptin may mediate at least part of the protective effect of fat mass on the skeleton.
This hypothesis is further supported by our in vitro data
showing that leptin significantly increased OPG mRNA steady state
levels and protein production, whereas it decreased RANKL mRNA
expression by human marrow stromal cells. Transgenic mice
overexpressing OPG (21) have generalized increased bone
mass (osteopetrosis) due to decreased osteoclastogenesis and bone
resorption, whereas OPG-deficient mice have severe osteoporosis due to
increased osteoclastogenesis and bone resorption (38).
Takahashi et al. (39) showed that leptin
induced MAPK-dependent cell proliferation in the mouse embryonic cell
line C3H10T1/2. Interestingly, activation of MAPK enhanced osteoblastic
differentiation, whereas it induced phosphorylation of PPAR
, which
prevented adipogenesis. Indeed, we showed that leptin inhibited
adipocyte differentiation of hMS cells, whereas it promoted
osteoblastic differentiation (18). On the other hand, we
demonstrated that the progression along this pathway resulted in
increased OPG mRNA levels and decreased RANKL mRNA in MSC
(40). Thus, regulation of the OPG/RANKL pathway by leptin
may be related to its differentiating effect on osteoblastic precursor
cells. Indeed, Takahashi et al. (40) showed
that leptin induced mitogen-activated protein kinase-dependent cell
proliferation in the mouse embryonic cell line C3H10T1/2.
Interestingly, activation of MAPK enhanced osteoblastic
differentiation, whereas it induced phosphorylation of PPAR, which
prevented adipogenesis. In accordance with our results, Holloway
et al. (41) recently reported that leptin was
able to inhibit osteoclastogenesis in vitro through an
increase in OPG mRNA and protein expression in human peripheral blood
mononuclear cells and a decrease in RANKL mRNA expression. A plausible
teleological explanation for the observed bone changes seen in rats may
be that high levels of circulating leptin are sensed by early bone
marrow precursor cells as a signal that extra fat is being accumulated,
and there will be a need for bone formation to bear this extra fat.
Interestingly, in humans, physiological situations such as puberty and
pregnancy, characterized by body weight gain, are associated with
increased leptin levels (13, 42, 43).
Recently, Ducy et al. (23) showed that ob/ob and db/db mice have an increased bone mass despite hypogonadism and hypercortisolism. Furthermore, the intracerebroventricular infusion of leptin caused bone loss in leptin-deficient mice, suggesting that leptin is a potent inhibitor of bone formation acting through the central nervous system. Contrary to these studies, Steppan et al. (24) showed that leptin administration led to a significant increase in femoral length, total body bone area, bone mineral content, and bone density in ob/ob mice compared with those in vehicle-treated controls. This increase in total body bone mass was the result of an increase in both trabecular and cortical bone mass. Several factors may explain these discrepancies. The deficiency of leptin during development (24) may somehow impair postnatal development and response to leptin administration. In fact, there is growing evidence that leptin largely produced by the placenta (44) could play a significant role during fetal growth (45).
Supporting the hypothesis that leptin may have positive effects on bone metabolism, a recent study by Ogueh et al. has shown that there is a negative correlation between fetal leptin levels and levels of cross-linked carboxyl-terminal telopeptide of type I collagen, a marker of bone resorption (46). They postulated that leptin decreased bone resorption with the overall effect of increasing bone mass in humans. They concluded that leptin might play a role in fetal bone metabolism as part of its effect on fetal growth and development.
The route of leptin administration is an obvious difference between Ducy’s studies and others. Thus, to reconciliate these different results, we postulated that leptin effects on bone may result from a balance between negative central effects and positive peripheral effects. In fact, the concept of leptin resistance (47) that could occur with the development of obesity despite increasing levels of leptin is at least partly related to the observed decrease in blood-brain barrier permeability (48, 49, 50). The serum levels of leptin may also modulate this balance, as we observed that serum leptin levels were correlated with BMD in women, but not in men, with leptin levels 2- to 3-fold higher in the former.
Ducy et al. (23) have recently shown that ob/ob and db/db mice have increased bone mass despite hypogonadism and hypercortisolism. Moreover, the intracerebroventricular infusion of leptin caused bone loss in leptin-deficient mice. The researches postulated that leptin is a potent inhibitor of bone formation acting through the central nervous system. The findings of the present study would suggest that leptin has a protective peripheral skeletal effect, and it may be that overall leptin effects on bone result from a balance between negative central effects and positive direct peripheral effects depending on serum leptin levels or blood-brain barrier permeability. There may be also important species differences in rats compared with mice with regard leptin action on bone.
Anorexia nervosa (AN) is characterized by a very similar hormonal profile to that of ob/ob mice with hypercorticism, hypogonadism, and a dramatic decrease in serum leptin levels. However, the features of AN include osteoporosis, which is more severe than the bone loss secondary to hypothalamic amenorrhea and is critically dependent upon nutritional factors in addition to the degree or duration of estrogen deficiency itself (51). Interestingly, Karlsson et al. (52) recently reported that AN occurring during adolescence impaired both mineral accrual, as measured by volumetric BMD (vBMD), and bone size. More importantly, whereas reduced volumetric BMD may be related to estrogen deficiency, reduced bone size no longer existed after adjusting for fat and lean masses. Weight, but not estrogen use, is a significant predictor of BMD in anorexic women at all skeletal sites (53). Overall, these data suggest that the dramatic decline in leptin levels observed during AN may be one of the major hormonal factors in the pathogenesis of the associated bone fragility through diminishing cortical BFR and skeletal growth.
Based on our data, we believe that leptin may play an important protective role in bone metabolism by inhibiting bone resorption. Consequently, it could be a major contributing factor to the protective effect of obesity against osteoporosis. The results obtained from these studies may have significant implications in understanding the mechanisms involved in the osteogenic effects exerted by obesity as well as for the therapy of osteoporosis. Studies are needed to evaluate whether leptin therapy of postmenopausal women can prevent bone loss-associated estrogen deficiency.
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Acknowledgments |
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Footnotes |
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1 Current address: INSERM, E9901, University Hospital, St.
Etienne 42055, France. 
Abbreviations: AN, Anorexia nervosa; BFR, bone formation rate; BMD, bone mineral density; BV/TV, cancellous bone volume; FBM, fat body mass; hMS, human marrow stromal; MAR, mineral apposition rate; MSC, marrow stromal cells; OVX, ovariectomy/ovariectomized.
Received January 25, 2001.
Accepted for publication April 25, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not interleukin-6 stimulate osteoprotegerin ligand gene expression
in human osteoblastic cells. Bone 24:255–259[CrossRef]
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