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J Bone Miner Res. Apr 2008; 23(4): 536–543.
Published online Nov 10, 2007. doi:  10.1359/JBMR.071202
PMCID: PMC2669161

Impact of Glucose-Dependent Insulinotropic Peptide on Age-Induced Bone Loss


GIP is an important hormonal link between nutrition and bone formation. We show for the first time that BMSCs express functional GIP receptors, that expression decreases with aging, and that elevations in GIP can prevent age-associated bone loss.


We previously showed that C57BL/6 mice lose bone mass as they age, particularly between 18 and 24 mo of age. The mechanisms involved in this age-dependent induced bone loss are probably multifactorial, but adequate nutrition and nutritional signals seem to be important. Glucose-dependent insulinotropic peptide (GIP) is an enteric hormone whose receptors are present in osteoblasts, and GIP is known to stimulate osteoblastic activity in vitro. In vivo, GIP-overexpressing C57BL/6 transgenic (GIP Tg+) mice have increased bone mass compared with controls. Bone histomorphometric data suggest that GIP increases osteoblast number, possibly by preventing osteoblastic apoptosis. However, potential GIP effects on osteoblastic precursors, bone marrow stromal cells (BMSCs), had not previously been examined. In addition, effects of GIP on age-induced bone loss were not known.

Materials and Methods

Changes in BMD, biomechanics, biomarkers of bone turnover, and bone histology were assessed in C57BL/6 GIP Tg+ versus Tg (littermate) mice between the ages of 1 and 24 mo of age. In addition, age-related changes in GIP receptor (GIPR) expression and GIP effects on differentiation of BMSCs were also assessed as potential causal factors in aging-induced bone loss.


We report that bone mass and bone strength in GIP Tg+ mice did not drop in a similar age-dependent fashion as in controls. In addition, biomarker measurements showed that GIP Tg+ mice had increased osteoblastic activity compared with wildtype control mice. Finally, we report for the first time that BMSCs express GIPR, that the expression decreases in an age-dependent manner, and that stimulation of BMSCs with GIP led to increased osteoblastic differentiation.


Our data show that elevated GIP levels prevent age-related loss of bone mass and bone strength and suggest that age-related decreases in GIP receptor expression in BMSCs may play a pathophysiological role in this bone loss. We conclude that elevations in GIP may be an effective countermeasure to age-induced bone loss.

Key words: glucose-dependent insulinotropic peptide, bone, transgenic mice, bone marrow stromal cells, aging


Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone with anabolic effects on multiple tissues.(1) We have previously described GIP effects on bone cells, including effects on both osteoblasts(2) and osteoclasts.(3) GIP stimulates collagen type I synthesis and increases alkaline phosphatase activity in osteoblasts consistent with an anabolic effect on these cells.(2) In addition, GIP inhibits osteoclastic differentiation and activity.(3) The net effect in vivo is that elevations of GIP result in an increase in bone mass,(4) whereas the absence of GIP signaling results in significantly lower bone mass.(5,6) We have previously reported on the development and characterization of GIP-overexpressing transgenic (Tg+) mice.(4,7) These Tg+ mice have increased bone mass consistent with our in vitro data showing stimulatory GIP effects on osteoblasts and inhibitory effects on osteoclasts. Although GIP is only one of several enteric hormones that can modulate bone mass,(8,9) our data are consistent with GIP being an important hormonal link between nutrient ingestion and bone formation.(8,9)

The causes of aging-induced bone loss are not fully understood but seem to be multifactorial. Bone regeneration occurs through continuous bone cell renewal from bone marrow progenitor cells. It has been proposed that changes in this progenitor cell pool with aging could result in osteoporosis.(10) In fact, we have shown that aging leads to changes in both progenitor cell number and differentiation capacity in C57BL/6 mice.(11) We and others have previously shown that the C57BL/6 mouse is a valid model to study age-induced bone loss.(1214) These mice begin to lose bone after 18 mo of age and have large drops in bone mass by 29 mo of age.(14) Because of the well-established association between nutrition and aging (e.g., reduced nutrient intake in the form of caloric restriction is the countermeasure most consistently shown to prolong lifespan), we hypothesized that the GIP Tg+ mice would be protected from age-induced bone loss. We show that the GIP Tg+ mice do have higher bone mass than controls and that this difference in bone mass continues to increase with increasing age. To examine potential underlying mechanisms for this effect, we measured GIP receptor expression bone marrow progenitor cells and showed an age-dependent decrease in receptor expression. Taken together, these data suggest that GIP may be an effective countermeasure to age-induced bone loss.




We previously reported on the generation of GIP-overexpressing transgenic mice (Tg+).(4,7) In brief, Tg and Tg+ mice were bred and maintained on a C57BL/6 genetic background. The Tg mice used were littermates of the Tg+ mice. Mice were kept in cages of four animals per cage at 25°C with a 12/12-h light/dark cycle. They had free access to a standard diet [Harlan TakLad Rodent Diet (W) 8604] and water ad libitum during the entire experiment. All experiments, which were approved by the Institutional Animal Care and Use Committee at Medical College of Georgia (Augusta, GA, USA), were performed with male mice.

Bone densitometry and body structure measurements:

BMD, BMC, scanned area, and lean and fat percentage were measured by DXA (Piximus system; GE LUNAR, Madison, WI, USA) between 9:00 a.m. and 12:00 p.m. as previously reported.(6)

Biochemical measurements:

Biochemical measurements were performed as previously reported.(6) Briefly, blood was obtained from the retro-orbital sinus using unheparinized capillary pipettes and collected into Microtainer tubes between 9:00 and 11:00 a.m. after an overnight fast. Serum concentrations of alkaline phosphatase activity (ALP), glucose, and Ca2+ were assayed on a Modular Analytics SWA system with Roche reagents at the VA Medical Center, Augusta, GA. The serum concentration of osteocalcin was measured using an enzyme immunoassay (EIA) kit (Biomedical Tech, Stoughton, MA, USA). The serum concentration of pyridinoline cross-links (PYD) was determined using an EIA kit (Quidel Corp., San Diego, CA, USA). The serum concentration of GIP was also measured using a mouse GIP EIA kit (LINCO Research, St Charles, MO, USA).

Biomechanical testing:

Bone biomechanical measurements were performed as previously described.(6) Briefly, biomechanical properties were evaluated using the left femora of 12- and 24-mo-old GIP Tg and Tg+ mice using a three-point bending test. Femora were placed in a mechanical testing machine on two supports separated by a distance of 5 mm, and load was applied to the middle of the shaft. The mechanical resistance to failure was tested using a servo-controlled electromechanical system (Instron Corp., High Wycombe, UK). The actuator was displaced at a rate of 100 μm/s. Both displacement and load were recorded. The following parameters were derived from the force-displacement curve: (1) ultimate force (Fu), representing the strength of the bone; (2) ultimate displacement (δu), representing the ductility; and (3) work to failure (U), determined as the area under the load-displacement curve, representing the energy the bone can absorb before breaking. These parameters indicate the bone's extrinsic biomechanical properties at an organ level. For the intrinsic properties, the following parameters were calculated as previously described(15): (1) ultimate stress (σu); (2) ultimate strain (εu); and (3) modulus of toughness (u). These values represent the strength, ductility, and absorbed energy of bone at a tissue level, respectively.

Bone sections:

Bone sections were obtained and processed as previously described,(16) and the histomorphometric measurements were also made as described.(17) In brief, the right femur and tibia were dissected free and fixed in 70% ethanol. Once bones were fixed in 70% ethanol, the bones were cut across the proximal one third of the shaft using a diamond wire saw. The bones were dehydrated and embedded in methyl methacrylate (MMA). Plastic blocks were sectioned at 6–8 μm using a Leitz Polycut S microtome.

Progenitor cell isolation:

Bone marrow cells were isolated as previously described.(18) Briefly, male C57BL/6 mice were purchased from the aged rodent colony at the National Institute on Aging (Bethesda, MD, USA). Femora and tibias were dissected free of soft tissues, cut open at both ends, and flushed with complete isolation media (CIM; consisting of RPMI-1640 supplemented with 9% FBS, 9% horse serum, 100 U/ml penicillin, 100 μg/ml streptomycin, and 12 μM l-glutamine, 2 ml/mouse)(19) using a 22-gauge syringe followed by filtration through a 70-μm nylon mesh filter. Marrow aspirates were pooled and used for bone marrow stromal cell (BMSC) isolation. The BMSCs were isolated using a protocol modified from Gimble et al.,(20) Peister et al.,(19) and Tropel et al.(21) The single-cell suspension was plated in 175-cm2 flasks at a density of 2 × 107 cells/flask. After a 3-h incubation at 37°C in 5% CO2, the media containing nonadherent cells were removed, and the adherent cells were washed two times gently with PBS to reduce the degree of hematopoietic lineage cell contamination. The cells were cultured in CIM for 3–4 wk with media changes every 3–4 days. At 70–80% confluence, the cells were lifted by incubation with trypsin/EDTA, washed, and resuspended at 5 × 106 cells/ml in PBS containing 0.5% BSA and 2 mM EDTA. Fifty microliters each of magnetic nanoparticles conjugated with anti-mouse CD11b, CD45R/B220, and Pan DC monoclonal antibodies were added to every 1 × 107 total cells. The mixture of cells and antibody-conjugated microbeads were incubated at 12°C for 30 min and placed on the IMagnet (BD Biosciences Pharmingen) for 8 min at room temperature to allow magnetic beads to migrate and attach to one side of the tube. The cells that were negative for these four antigens remained in solution and were collected and subjected to a round of positive-selection using anti-stem cell antigen-1 (Sca-1) microbeads. After several washes, the tubes containing cells were removed from the magnetic field, and the Sca-1–reactive cells were collected, plated at a density of 50–100 cells/cm2, and amplified using regular growth media (DMEM with 10% FBS).

Quantitative PCR:

Total RNA was extracted and DNase-treated using RNeasy Mini Kit (Qiagen Corp.) according to the manufacturer's protocol. Two micrograms of total RNA each was reverse transcribed to cDNA using SuperScript III First-Strand Synthesis System with Oligo(dT)20 as primer in a 20-μl reaction volume. mRNA levels were quantified with the LightCycler FastStart DNA Master SYBR Green I (Roche). The specificity was confirmed by melting curve analysis and electrophoresis of PCR products.


Osteoblastic differentiation:

BMSCs were plated in 96-well plates in triplicate at a density of 1500 cells/cm2. When the cells reached confluence, they were treated with osteogenic induction media (OS) consisting of regular growth media (DMEM plus 50 μM ascorbic acid-2-phosphate, 5 mM β-glycerophosphate, and 10 nM dexamethasone). The cells were cultured in OS continuously with fresh media replaced every third day. For alkaline phosphatase staining, 10 days after treatment the cells were fixed with 3.7% formaldehyde and stained with SIGMA FAST BCIP/NBT Buffered Substrate (B5655; Sigma-Aldrich) or Fast red violet (86C-1KT; Sigma-Aldrich) according to the manufacturer's instructions. For von Kossa staining, cells were labeled 21 days after the treatment was initiated. BMSCs were washed using calcium- and phosphate-free saline solution, fixed, and stained with 5% silver nitrate solution for 30 min at room temperature in the dark. BMSCs were washed gently with double-distilled water, exposed to UV light or bright sunshine for 30 min, and counterstained with 0.1% eosin. Quantification of alkaline phosphatase staining and von Kossa were done using NIH Image J software, version 1.38.


Results are expressed as mean ± SE. Experiments were performed in triplicate except where noted. Data were analyzed using either ANOVA with Bonferroni posthoc testing or unpaired t-tests, using a commercial statistical package (Instat; Graphpad, San Diego, CA, USA).


GIP overexpression does not affect body weight or length

Because GIP is an anabolic hormone, there was the potential concern that persistent elevation in GIP levels might lead to increases in mouse weight or growth. However, as shown in Fig. 1, there was no statistical difference between Tg and Tg+ mice between 1 and 24 mo of age in either body weight (Fig. 1A, top) or total length (Fig. 1A, bottom). Similarly, there was no difference in lean body mass between the Tg and Tg+ mice (data not shown). Curiously, there was a tendency for the Tg+ mice to have a lower fat mass than Tg mice, which was statistically significant in mice of 3 and 9 mo of age, but by 16 mo of age, there was no difference between Tg and Tg+ mice (Fig. 1B).

FIG. 1
Body weight and length are not different between Tg and Tg+ mice. Tg and Tg+ mice at 1, 3, 6, 9, 16, and 24 mo of age (n = 12/time point) had body weight and length measured longitudinally. There was no statistically significant difference ...

Biochemical measurements in Tg+ and Tg mice

In our initial reports on the Tg+ mice, we found that the GIP gene was overexpressed in a wide variety of tissues and that mouse serum GIP levels were significantly elevated(4,7); however, we had not previously reported serum GIP levels at different ages. We found that GIP levels in the Tg+ mice were significantly higher than Tg mice at all ages. The highest GIP levels were seen in the younger mice (4 mo), and the levels appeared to plateau by 12 mo (Fig. 2A). Because GIP is an incretin hormone and GIP levels might affect glucose concentration, glucose was also measured; however, there was no significant difference between Tg and Tg+ mice (data not shown). GIP has also been reported to have an effect on calcium levels, with GIP receptor knockout mice having higher postprandial calcium values than wildtype mice.(5) However, at least under fasting conditions, there were no age-related differences between Tg and Tg+ mice (data not shown).

FIG. 2
High GIP levels increased osteocalcin levels. Serum GIP levels in Tg+ and Tg mice were measured at 4, 12, and 24 mo of age (A, n = 12 mice/time point). GIP levels in the Tg+ mice were much higher than those in the Tg mice; the levels ...

To gain some insight into the mechanism responsible for previously observed changes in BMD, we next measured serum biomarkers of bone formation and breakdown. Osteocalcin is a 49 amino acid protein secreted by osteoblasts that is thought to reflect bone formation. As shown in Fig. 2B, the Tg+ mice had significantly higher levels of osteocalcin than Tg mice starting at 6 mo, and values remained significantly higher than those of Tg mice through 24 mo of age. In contrast, alkaline phosphatase, another marker of bone formation, was not different between Tg and Tg+ mice at any age (data not shown).

Serum PYDs (pyridinoline cross-links) are derived from collagen type I breakdown and are a reflection of bone breakdown. At 6 mo, the Tg mice had a significantly higher serum PYD level than Tg+ mice (Fig. 2C), consistent with suppression of bone breakdown in the Tg+ mouse; however, PYD levels at the other ages were not significantly different between Tg+ and Tg mice.

GIP overexpression increases BMD, which increases with increasing animal age

In our initial report on GIP Tg+ mice, we found that the Tg+ mice had a significantly higher bone mass than Tg mice at 4 mo of age.(4) We had also previously reported that as normal C57BL/6 mice age they lose bone, especially between 18 and 24 mo of age.(14) In the next set of experiments, we followed BMD serially over time and found that, starting at 4 mo of age, Tg+ mice had a significantly higher bone mass than Tg mice (Fig. 3A). Of note, however, is that the difference in total BMD between Tg and Tg+ mice actually increased over time. Thus, at 6 mo of age, there was about a 3.4% difference in BMD between Tg and Tg+ mice; however, at 24 mo of age, there was an 11% difference in their BMD measurements (corresponding differences in BMCs were 7% at 6 mo and 22% at 24 mo). To better define the major site of GIP action, we measured changes in BMD at different sites including the spine (Fig. 3B) and femur (Fig. 3C). Differences in BMD at the femur between Tg and Tg+ mice became significant at 6 mo of age and increased with increasing animal age (5.8% difference between Tg+ and Tg mice at 6 mo and 16% at 24 mo of age). In contrast, spine BMD in the Tg+ mice was higher compared with Tg mice at all time points after 3 mo of age but did not achieve statistical significance. To further assess the changes in bone quality induced by the high GIP levels, we next measured biomechanical parameters in relationship to mouse age.

FIG. 3
Tg+ mice have higher bone mass than Tg mice. Total BMD (A) was measured in Tg+ and Tg mice at 1, 3, 6, 9, 16, and 24 mo of age (n = 12 mice/time point). Starting at 6 mo, Tg+ mice had significantly higher BMD than Tg mice. BMD ...

GIP overexpression increases bone strength in mice at 12 and 24 mo of age

BMD measurements do not provide any information on bone strength or bone quality. Bone strength was measured using a three-point bending system, and we found that even though Tg+ mice had significantly higher BMD and BMC measurements than Tg mice at 12 mo of age, there was no significant difference in the biomechanical measurements except for modulus of toughness at break, which was actually lower (Fig. 4). However, at 24 mo of age, bones from Tg+ mice were significantly stronger than those from Tg mice. Tg+ bones at 24 mo had significant increases in ultimate force required for break (Fig. 4A), ultimate displacement at break (Fig. 4C), ultimate strain at break (Fig. 4D), work to failure (Fig. 4E), and modulus of toughness (Fig. 4F). An issue of potential concern is whether differences in nutritional intake related to the aging process could account for the observed differences in biomechanical properties between mice of 12 and 24 mo of age. However, as stated above, there were no differences between the mice in weight or lean body mass, suggesting that nutritional status was the same in both groups.

FIG. 4
Multiple biomechanical measurements of Tg+ mice at 24 mo of age were significantly higher than those of Tg mice. At 12 mo of age, there were no significant differences between Tg and Tg+ mice in either ultimate force at break (A), ultimate ...

GIP promotes osteoblastic differentiation in BMSCs, whereas GIP receptor expression decreases with age

Data from Fig. 2B suggested that the increases in BMD observed in Fig. 3 were primarily related to increased bone formation rather than a decrease in bone breakdown. Consistent with these results, bone histomorphometry results by Tsukiyama et al.(5) showed that the main site of action for GIP-related increases in bone formation was the osteoblasts, apparently by increasing osteoblast number by preventing apoptosis. We examined bones from Tg versus Tg+ mice and also observed that the Tg+ mice had an increased number of osteoblasts (Fig. 5).

FIG. 5
Osteoblast number is increased in Tg+ mice versus Tg mice at 24 mo of age. Micrographs shown are transverse sections of the distal femur from Tg+ and Tg mice showing increased osteoblastic number in the Tg+ (B) vs. Tg mice (A). ...

Osteoblast number can be increased by either decreased cell death or increased formation. Thus, we next examined whether GIP had any effect on BMSC differentiation to osteoblasts. Interestingly, we found that the GIP receptor was expressed in BMSCs from young mice (6 mo) to the same extent as that we had previously reported for osteoblasts.(2) However, as the mice aged (between 6 and 24 mo of age), GIPR expression decreased by >5-fold (Fig. 6A). To determine whether the GIP receptors expressed on BMSCs were functional and what their role was, we examined the effects of addition of GIP (1 nM) on BMSC differentiation. Two indices used to examine BMSC differentiation into osteoblasts are alkaline phosphatase staining (Fig. 6B) and mineralized nodule formation (von Kossa, Fig. 6C). As can be seen, GIP significantly stimulated BMSC differentiation into the osteoblastic pathway.

FIG. 6
GIPR expression decreases in an age-dependent manner and GIP stimulates BMSC differentiation into osteoblasts. (A) BMSCs were examined for GIP receptor transcript expression by real-time PCR. GIPR copy number normalized to 1 at 6 mo showed a decrease ...


Taken together, our data showed that not only is GIP able to increase bone mass as we have previously reported,(4) but that GIP's effect on increasing bone mass seems to be more pronounced as the animals age (difference in BMD of the C57BL/6 Tg versus Tg+: 3.4% difference at 6 mo versus 11% at 24 mo). In addition, much of the increase in total bone mass seems to be related to changes in cortical bone, as shown by the changes in BMD in the femur. Interestingly, the separation in BMDs between young and old animals is not caused by continued increases in Tg+ bone mass but rather by the prevention of the age-related declines in BMD seen in the Tg mice. We have previously shown that C57BL/6 mice between the ages of 18 and 24 mo show very significant declines in BMD,(14) and GIP seems to be able to prevent the bone loss occurring between these ages. Our biomechanical data are consistent with this BMC data. At 12 mo of age, the bones of the Tg+ were not any stronger than those of the Tg mice. In contrast, at 24 mo, the bones of Tg+ mice were stronger than those of Tg mice. However, the effect of high GIP levels seems to be to prevent the loss of bone strength that occurs in the control animals between 12 and 24 mo of age (i.e., GIP overexpression resulted in the bone strength of the older animal being maintained at that of a younger animal).

It is well established that nutrition and nutrition-related hormones are very important in bone growth and in maintaining bone mass.(8,9) Our results showed that osteoblast progenitor cells (BMSC) seem to be losing their responsiveness to at least one nutritional signal, GIP, as shown by the large age-dependent drops in GIP receptor expression. We and others(5,6) have shown that loss of GIP receptor expression results in dramatic bone loss and decreases in osteoblastic number and function. These data showed that at least part of the previously reported effects on osteoblast number are caused by GIP-induced increases in osteoblast differentiation from osteoblastic progenitor cells. Furthermore, our data suggest that the aging process itself results in GIP receptor downregulation and that increasing GIP levels in the transgenic mouse compensates for this decreased GIPR expression and thus prevents the bone loss seen in the control mice between 12 and 24 mo of age.

Our Tg mice are fed ad libitum and eat multiple times while they are awake, so presumably they have repeated nutrient-induced elevations of GIP during this time. Thus, at younger mouse ages, the effects of GIP overexpression on bone mass are presumably caused by the pharmacologic elevations in GIP. However, as these mice age, GIP effects on bone mass potentially reflect a physiological one, because the GIP receptor is downregulated. It is unclear what factors are responsible for the GIPR downregulation observed in the BMSCs, although we speculate that it may be related to chronic overnutrition. Evolutionarily, both humans and animals obtained nutrition on an intermittent basis related to availability and dependent on their foraging, and it is only recently that overnutrition has become a problem. Caloric restriction has been shown to upregulate the insulin receptor,(22) and whether caloric restriction would similarly upregulate the age-induced decreases in GIP receptor expression in BMSCs is not known.

In summary, this study showed that BMSC express GIP receptors, that there is an age-dependent decrease in GIPR expression, and that elevations in GIP levels prevent age-induced decreases in osteoblast number, bone mass, and bone strength. These data suggest that loss of nutritional hormone signaling may play a causal role in age-induced bone loss.


This work was supported in part by National Institutes of Health Grants R01DK058680 to CMI and R01AR049717 to MWH.


The authors state that they have no conflicts of interest.


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