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Molecular Endocrinology 20 (7): 1644-1651
Copyright © 2006 by The Endocrine Society

Gastric Inhibitory Polypeptide as an Endogenous Factor Promoting New Bone Formation after Food Ingestion

Katsushi Tsukiyama, Yuichiro Yamada, Chizumi Yamada, Norio Harada, Yukiko Kawasaki, Masahito Ogura, Kazuhisa Bessho, Minqi Li, Norio Amizuka, Masahiro Sato, Nobuyuki Udagawa, Naoyuki Takahashi, Kiyoshi Tanaka, Yutaka Oiso and Yutaka Seino

Departments of Diabetes and Clinical Nutrition (K.Ts., Y.Y., C.Y., N.H., Y.K., M.O., Y.S.) and Oral and Maxillofacial Surgery (K.B.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Division of Oral Anatomy (M.L., N.A.), Department of Oral Biological Science, Niigata University Graduate School for Medical and Dental Sciences, Center for Transdisciplinary Research, Niigata University, Niigata 951-8514, Japan; Department of Biochemistry (M.S., N.U.) and Institute for Oral Science (N.T.), Matsumoto Dental University, Nagano 399-0781, Japan; Department of Nutrition (K.Ta.), Kyoto Women’s University, Kyoto 605-8501, Japan; Department of Endocrinology and Diabetology (K.Ts., Y.O.), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; and Kansai Electric Power Hospital (Y.S.), Osaka 553-0003, Japan

Address all correspondence and requests for reprints to: Dr. Yuichiro Yamada, Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: yamada{at}metab.kuhp.kyoto-u.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body’s calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR–/–) were significantly lower than those of wild-type (GIPR+/+) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR–/– mice, indicating that GIPR–/– mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR–/– mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
OSTEOPOROSIS IS THE major cause of fractures in elderly men and women, and is a growing health care problem in the world (1). In addition to its structural role, bone serves as the body’s nutrient reserve of calcium to maintain blood calcium levels. Locally, this function is accomplished through continuous tissue renewal, called bone remodeling (2, 3, 4). Old bone is continuously resorbed by the hematopoietically derived osteoclasts, and new bone is formed from the mesenchyme-derived osteoblasts. Such intercellular communication between osteoblasts and osteoclasts is crucial in bone remodeling.

Ingested calcium is crucial for bone health throughout life. Even in the satiate present, calcium is still insufficient and the elderly are much more likely to have insufficient calcium intake (5). Calcium alone is partially effective in preventing bone loss (6, 7, 8). However, besides the epidemiological data, little is known about the molecular mechanisms of calcium metabolism, especially the pathway from calcium derived from food to calcium deposition in bone.

Gastric inhibitory polypeptide (GIP) is a gastrointestinal peptide hormone of 42 amino acids that is released from duodenal endocrine K cells after absorption of glucose or fat (9, 10). GIP was originally isolated from porcine intestine on the basis of its ability to inhibit gastric acid secretion (11), and subsequent studies of GIP revealed that GIP potentiates glucose-induced insulin secretion from pancreatic ß-cells (12), so GIP also is referred to as glucose-dependent insulinotropic polypeptide. We have isolated a human cDNA and gene encoding the GIP precursor and the human GIP receptor (GIPR) (13, 14, 15), confirming that GIP belongs to the vasoactive intestinal peptide/glucagon/secretin family.

The GIPR has seven potential membrane-spanning domains, a feature characteristic of G-protein-coupled receptors and is expressed in various cells including pancreatic ß-cells, adipocytes, and osteoblasts (16). We have developed mice with a targeted mutation of the GIPR gene (GIPR–/–) and revealed that insulin secretion from the pancreatic ß-cells is regulated not only by glucose but also by GIP, especially in the early phase after glucose ingestion and that GIP is the major insulinotropic factor in response to oral glucose loading in ATP-sensitive potassium channel-deficient mice (17, 18). Furthermore, GIP directly stimulates nutrient uptake into adipocytes and GIPR–/– mice fed a high-fat diet were clearly protected from obesity and insulin resistance, indicating that GIP promotes the efficient storage of ingested fat (19). Here, we investigate the role of GIP on osteoblasts and revealed that GIP promotes the efficient storage of ingested calcium into bone. Because intermittent administration of PTH can effectively prevent osteoporotic fractures (20, 21), intermittently elevation of blood GIP levels elicited by meals plays a crucial role on preventing pathogenesis and development of osteoporosis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
No Effect of GIP Signaling on Endochondral Ossification
The longitudinal bone growth was determined by endochondral ossification in the cartilaginous growth plate. GIPR–/– mice have similar naso-anal length to wild-type (GIPR+/+) mice (Fig. 1AGo). Soft x-ray analysis showed that longitudinal growth of limb bones is not affected in GIPR–/– mice (Fig. 1BGo). These observations indicate that GIP signaling does not affect endochondral ossification.


Figure 1
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  		Fig. 1. Effects of GIP on Endochondral Ossification

A, Growth of GIPR+/+ and GIPR–/– mice at 10 wk of age. B, Soft x-ray analyses of GIPR+/+ and GIPR–/– mice.

 
Inhibition of GIP Signaling Causes Thinner Bone Trabeculae
Histological analyses of 8-wk-old male mice showed thinner trabeculae in the bones of GIPR–/– mice compared with those of GIPR+/+ mice (Fig. 2Go, A and B), and the phenotype was observed in both sexes and was also observed in femurs (data not shown).


Figure 2
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  		Fig. 2. Effects of GIP on Bone Trabeculae

Histological analyses of tibiae from GIPR+/+ mice and GIPR–/– mice. The tibiae of 8-wk-old male mice were examined. Original magnification: A, x40; B, x100.

 
Inhibition of GIP Signaling Causes Decreased Osteoblastic Bone Formation and Increased Osteoclastic Bone Resorption
Histochemical analyses showed that the number of osteoblasts in GIPR–/– mice was similar to that in GIPR+/+ mice (Fig. 3AGo), and the number of osteoclasts was increased in GIPR–/– mice (Fig. 3BGo), which is consistent with the increased urinary elimination of deoxypyridinoline cross-link, a biochemical marker of bone resorption, in GIPR–/– mice (Fig. 4AGo). These phenotypes were observed in both sexes and were also observed in femurs (data not shown). We performed the bone histomorphometrical analyses of younger GIPR+/+ and GIPR–/– mice (6 wk old) and quantified the skeletal phenotype (Table 1Go). The trabeculae tended to be thinner in GIPR–/– mice, and cellular activity parameters about bone formation revealed that bone formation parameters in GIPR–/– mice were significantly lower than those of GIPR+/+ mice (Table 1Go). On the other hand, cellular activity parameters about bone resorption, such as the number of osteoclasts, especially multinuclear osteoclasts, which are the fully differentiated cells and are responsible for active bone resorption, were significantly increased in GIPR–/– mice (Table 1Go). These changes observed in GIPR–/– mice indicate decreased osteoblastic bone formation and increased osteoclastic bone resorption.


Figure 3
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  		Fig. 3. Dysregulation of Bone Remodeling in GIPR–/– Mice

Immunostaining of TNAPase (A) and tartrate-resistant acid phosphatase staining (B) of tibiae from GIPR+/+ and GIPR–/– mice are shown.

 

Figure 4
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  		Fig. 4. Effects of GIP on Calcium Homeostasis in Vivo

A, Urinary elimination of deoxypyridinoline cross-links from GIPR+/+ (open column) and GIPR–/– (filled column) mice. Values are means ± SE. *, P < 0.05 for GIPR+/+ mice vs. GIPR–/– mice. B, Plasma calcium concentration of GIPR+/+ and GIPR–/– mice before (open) and after (filled) meal is shown. Values are means ± SE. *, P < 0.05 vs. fasting.

 

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  		Table 1. Bone Histomorphometry of Tibiae of GIPR+/+ and GIPR–/– Mice

 
Effect of GIP Signaling on Calcium Homeostasis
We compared the calcium concentrations before and after meal ingestion. GIPR+/+ mice showed no significant difference in the fasting and fed plasma calcium concentration (Fig. 4BGo). In contrast, GIPR–/– mice had similar levels of plasma calcium before meal ingestion, but had higher levels after meal ingestion (Fig. 4BGo). These findings and the results of cellular activity parameters about bone formation of GIPR–/– mice indicated that GIP directly links calcium contained in meal to calcium deposition on bone.

No Direct Effect of GIP on Osteoclasts
To determine whether the effects of GIP are the results of direct action of the hormone on the osteoclasts or indirect action mediated by osteoblasts, we investigated the effects of GIP using cell culture. First, we examined the effects of GIP on survival and pit-forming activity of mature osteoclasts (2). When crude osteoclast preparation was placed on dentine slices, many resorption pits were formed. Although calcitonin strongly inhibited pit formation by osteoclasts, GIP showed no inhibitory effect on the pit-forming activity of osteoclasts (Fig. 5Go, A and B). These results indicate that GIP does not directly inhibit osteoclasts function.


Figure 5
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  		Fig. 5. Effects of GIP on Pit-Forming Activity of Osteoclasts in Vitro

The crude osteoclast preparation was cultured on dentine slices in the presence or absence of GIP at 100 µM, using calcitonin as the positive control. A, The resorption pits formed on the slices were stained with Mayer’s hematoxylin solution for observation by light microscope (upper), or scanned by electron microscope (lower). B, The number of resorption pits was calculated.

 
Antiapoptotic Effect of GIP on Osteoblasts
Because osteoclast differentiation and function are regulated by osteoblasts (2), we examined the direct effects of GIP on osteoblasts. Treatment of Saos-2 cells, a human osteoblastic cell line, with GIP increased the intracellular concentration of cAMP, indicating functional expression of GIP receptors on Saos-2 osteoblastic cells (Fig. 6AGo). Exposure to etoposide, one of the representative proapoptotic reagents acting on osteoblasts, for 6 h induced apoptosis of Saos-2 cells, as indicated by the appearance of pyknotic nuclei (Fig. 6BGo). The percentage of cells undergoing apoptosis was significantly decreased by pretreatment of GIP or PTH (Fig. 6CGo). The antiapoptotic effect of GIP was dose dependent and still evident at 1 nM. The results of the same experiments using primary mouse osteoblasts confirmed that GIP prevents etoposide-induced apoptosis (Fig. 6DGo).


Figure 6
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  		Fig. 6. Effects of GIP on Preventing Apoptosis of Osteoblasts in Vitro

A, Saos-2 cells, a human osteoblastic cell line, were stimulated with the indicated concentrations of human GIP and human PTH for 30 min, and cAMP levels were measured. **, P < 0.01 vs. control. B, Saos-2 cells were cultured for 6 h with 50 µM etoposide in the absence or presence of preincubation for 1 h with 100 nM GIP. The pyknotic fragmented nuclei typical of apoptotic cells viewed using Hoechst 33342 fluorescent dye. Original magnification, x100. Insets, Percentage of cells undergoing apoptosis. C, Saos-2 cells were cultured for 1 h in the indicated concentration of GIP or PTH and then incubated for an additional 6 h in the absence (open) or presence of 50 µM etoposide (filled). Apoptotic cells were enumerated by trypan blue staining. Values are indicated as means ± SE. *, P < 0.05; **, P < 0.01 vs. etoposide alone. D, Primary mouse osteoblasts were cultured for 1 h with or without GIP and then incubated for an additional 6 h in the absence (open) or presence of 50 µM etoposide (filled). Apoptotic cells were enumerated by trypan blue staining. Values are indicated as means ± SE. **, P < 0.01 vs. etoposide alone.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
Calcium plays a fundamental role as second messenger in intracellular signaling. Ca2+ information is processed by sensor proteins, like calmodulin and Ca2+-sensitive enzymes, and transmitted to target molecules to exert a lot of biological effects. Therefore, blood calcium levels should be tightly controlled by proper balance between calcium intake from ingested meal and calcium excretion to urine and stool and bone serves as the body’s calcium reserve. Even in the satiate present, calcium is still insufficient and osteoporosis is a growing health care problem in the world. However, the molecular mechanism underlying the deposition of calcium from meal is little known.

Cyclic activation of cell surface receptors often leads to a different biological response than sustained activation. Continuous activation of PTH receptors by endogenous PTH functions to maintain normal extracellular calcium levels by enhancing osteoclastic bone resorption through activation of osteoblasts and liberation of calcium from the adult skeleton. In contrast, cyclic activation of PTH receptors by exogenous PTH when administered intermittently as a pharmacologic agent is known to exert an anabolic effect on bones (20, 21). Protecting osteoblasts from apoptosis has been reported to contribute (22, 23, 24). However, the physiological role of anabolic effects of PTH has not yet been determined. Considering that plasma GIP levels are greatly increased after meal ingestion (10), and that GIP, like PTH, protects osteoblasts from apoptosis, we hypothesized that GIP plays a physiological role in calcium metabolism in vivo.

The results of resorption pit assay indicated that GIP has no direct effects on mature osteoclasts. Therefore, primary site of GIP action is osteoblasts. We are supposing that, in GIPR–/– mice, osteoblasts are stimulated continuously by PTH and intermittently by GIP in vivo, and in GIPR–/– mice, osteoblasts are stimulated only by PTH. Continuous stimulation of PTH has been shown to induce increased bone resorption rather than decreased bone formation, consistent with our results. The differential responses of skeletal bone to intermittent elevation of endogenous GIP vs. continuous elevation of endogenous PTH, both of which increase the intracellular cAMP concentration, represent a systemic regulator of bone remodeling with important clinical and therapeutic implications (Fig. 7Go). Because GIP receptors are expressed in small intestine and administration of GIP inhibits gastrointestinal motility, it is possible that GIP inhibits intestinal calcium absorption. However, there have been no reports examining the effects of GIP on calcium absorption. Further examinations are required to elucidate the role of GIP on extra-bone tissues.


Figure 7
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  		Fig. 7. Schematic Model of Cyclic (GIP) and Persistent (PTH) Activation of Osteoblasts in Bone Remodeling

GIP induces a cyclic increase of the intracellular cAMP concentration ([cAMP]i) in osteoblasts that induces bone formation, calcium from the blood calcium pool depositing on bone. Endogenous PTH induces a persistent increase of [cAMP]i in osteoblasts that induces bone resorption, calcium from bone releasing into the blood calcium pool.

 
The metabolically thrifty GIP gene promotes not only the efficient storage of ingested fat (19) but also of ingested calcium, and the GIP signal represents a novel therapeutic strategy for anti-osteoporosis drugs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Animals
The generation of GIPR–/– mice was previously described (17, 18, 19). The Animal Care Committee of Kyoto University Graduate School of Medicine approved animal care and procedures.

Bone Histomorphometry
To assess the parameters for bone histomorphometry, 6-wk-old male mice were double-labeled with sc injections of 30 mg/kg of tetracycline hydrochloride (Sigma-Aldrich, St. Louis, MO) at 4 d before killing, and 10 mg/kg of calcein (Dojindo, Kumamoto, Japan) at 2 d before killing. Tibiae were removed from each mouse, and fixed with 70% ethanol. They were trimmed to remove the muscle, stained with Villanueva bone stain for 7 d, dehydrated in graded concentrations of ethanol, and embedded in methyll-methacrylate (Wako Chemicals, Kanagawa, Japan) without decalcification. Frontal plane sections (5 µm thick) of the proximal tibia were cut using a microtome (Leica, Nussloch, Germany). The cancellous bone was measured in the secondary spongiosa located 500 µm from the epiphyseal growth plate and 160 µm from the endocortical surface. Bone histomorphometric measurements of the tibiae were made using a semiautomatic image analyzing system (System Supply, Nagano, Japan) and a fluorescent microscope (Optiphot; Nikon, Tokyo, Japan) set at a magnification of x400. Standard bone histomorphometrical nomenclatures, symbols, and units were used as described in the report of the American Society for Bone and Mineral Research Histomophometry Nomenclature Committee (25). Statistical analysis was done using Student’s t test.

Histochemistry
The tibiae of 8-wk-old male mice were dissected free and immersed in the fixative at 4 C for 8 h. The specimens were then decalcified with 4.13% EDTA at 4 C for 2 wk, dehydrated with an increasing concentration of ethanol, and embedded in paraffin. Staining of dewaxed, paraffin-embedded tissue was performed according to previously published protocols (26, 27). For immunostaining of tissue nonspecific alkaline phosphatase (TNAPase), paraffin sections were incubated with rabbit serum to TNAPase and viewed using diaminobenzidine substrate by light microscopic observation. For tartrate-resistant acid phosphatase staining, specimens were rinsed with PBS and incubated in a mixture of 8 mg naphthol AS-BI phosphate (Sigma-Aldrich), 70 mg red violet LB salt (Sigma-Aldrich), and 50 mM L(+)-tartaric acid (0.76 g; Nacalai Tesque, Kyoto, Japan).

Osteoclast Assay
For resorption pit assay (28, 29), aliquots of crude osteoclast preparations were plated on dentine slices and cultured in {alpha}MEM (Sigma-Aldrich) supplemented with 10% fetal bovine serum with or without GIP (Peptide Institute, Osaka, Japan). Resorption pits on the dentine slices were visualized by staining with Mayer’s hematoxylin solution.

Osteoblast Assay
Osteoblasts grown from the calvarium of 2-d-old mice were collected by treatment of collagen gel cultures with collagenase (30). A human osteoblastic cell-line, Saos-2 cells (Dainippon Pharmaceutical, Osaka, Japan), and primary mouse osteoblasts were cultured in McCoy’s 5A modified medium (Life Technologies, Grand Island, NY) and {alpha}MEM, respectively, supplemented with 10% fetal bovine serum. Cells were treated with the indicated concentrations of human GIP and human PTH (Peptide Institute) for 1 h, and incubated for an additional 6 h in the presence or absence of 50 µM etoposide (Nipponkayaku, Tokyo, Japan). The pyknotic fragmented nuclei typical of apoptotic cells were viewed (31) using Hoechst 33342 (Sigma-Aldrich) and propidium iodide (Sigma-Aldrich) in an inverted fluorescence microscope with UV excitation at 340–380 nm (Axiovert 135; Carl Zeiss, Oberkochen, Germany). Apoptotic cells were enumerated by trypan blue (Life Technologies) staining (22).


   ACKNOWLEDGMENTS
 
We gratefully acknowledge Ms. Akemi Ito (Niigata Bone Science Institute, Niigata, Japan) for the measurement of bone histomorphometry.


   FOOTNOTES
 
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, by Health Sciences Research Grants for Comprehensive Research on Aging and Health from the Ministry of Health, Labor and Welfare, Japan, and by the Promotion of Niigata University Research Project.

First Published Online February 9, 2006

Abbreviations: GIP, Gastric inhibitory polypeptide; GIPR, GIP receptor; TNAPase, tissue nonspecific alkaline phosphatase.

Received for publication May 10, 2005. Accepted for publication February 2, 2006.


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 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

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A novel GIP receptor splice variant influences GIP sensitivity of pancreatic {beta}-cells in obese mice
Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E61 - E68.
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Q. Zhong, T. Itokawa, S. Sridhar, K.-H. Ding, D. Xie, B. Kang, W. B. Bollag, R. J. Bollag, M. Hamrick, K. Insogna, et al.
Effects of glucose-dependent insulinotropic peptide on osteoclast function
Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E543 - E548.
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Y. Yamada, K. Miyawaki, K. Tsukiyama, N. Harada, C. Yamada, and Y. Seino
Pancreatic and Extrapancreatic Effects of Gastric Inhibitory Polypeptide
Diabetes, December 1, 2006; 55(Supplement_2): S86 - S91.
[Abstract] [Full Text] [PDF]

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