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Endocrinology Vol. 138, No. 11 4959-4965
Copyright © 1997 by The Endocrine Society

ARTICLES

Osteoclasts Are Present in gp130-Deficient Mice1

Kojiro Kawasaki2, Yu-Hao Gao, Satoshi Yokose3, Yoshio Kaji, Toshitaka Nakamura, Tatsuo Suda, Kanji Yoshida, Tetsuya Taga4, Tadamitsu Kishimoto, Hiroko Kataoka, Takahito Yuasa, Hiromichi Norimatsu and Akira Yamaguchi

Departments of Oral Pathology (K.K., Y.G., S.Y., H.K., T.Y., A.Y.) and Biochemistry (T.S.), School of Dentistry, Showa University, Tokyo 142, Japan; Department of Orthopedic Surgery (K.K., H.N.), Kagawa Medical School, Kagawa 761–07, Japan; Department of Orthopedic Surgery (T.N.), School of Medicine, University of Occupational and Environmental Health, Fukuoka 807, Japan; Institute for Molecular and Cellular Biology (K.Y., T.T.), Osaka University, Osaka 565, Japan; Department of Medicine III (T.K.), Osaka University Medical School, Osaka 565, Japan; and Department of Orthopedic Surgery (T.Y.), Juntendo University School of Medicine, Tokyo, Japan

Address all correspondence and requests for reprints to: Akira Yamaguchi, Department of Oral Pathology, School of Dentistry, Showa University, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan. E-mail: akirayam{at}dent.showa-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Interleukin (IL)-6, IL-11, leukemia inhibitory factor, and oncostatin M similarly induce osteoclast formation in cocultures of osteoblastic cells and bone marrow cells. These cytokines share a common signal transducer, gp130, which forms a receptor complex with the specific receptor for each cytokine. To investigate the role of gp130 in osteoclast development, we examined bone tissues in gp130-deficient and wild-type newborn mice of the ICR background. Soft x-ray radiographs and microfocus x-ray computed tomographs revealed that bone marrow cavities were present in tibiae and radii of both wild-type and gp130-deficient mice. Microfocus x-ray computed tomography and histological examination demonstrated a decrease in the amount of trabeculae at the metaphysial region in tibiae and radii of the gp130-deficient mice compared with the wild-type mice. The number of osteoclasts in gp130-deficient mice was about double that in the wild-type mice. There were no apparent differences in the distributions of alkaline phosphatase-positive osteoblasts and the osteoid surface on the trabecular bone at the metaphysial region between the wild-type and gp130-deficient mice. The volume of mineralized trabecular bones was also decreased at mandibulae, accompanied by the increased number of osteoclasts in gp130-deficient mice compared with the wild-type and heterozygous mice. These results suggest that the formation of osteoclasts is not solely dependent on gp130 signaling, at least during fetal development. The osteoclastic bone resorption in gp130-deficient mice may be caused by the functional redundancy of bone-resorbing hormones and cytokines other than those of the IL-6 family.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CYTOKINES belonging to the interleukin (IL)-6 family such as IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor, and cardiotrophin-1 share several biological activities (1). The functional redundancy of these cytokines can be explained by the utilization of a common signal transducer, gp130, which forms receptor complexes with specific receptors for each cytokine (1).

Osteoclast development and function are regulated by various hormones and cytokines (2). Several lines of evidence have demonstrated important roles of cytokines belonging to the IL-6 family in osteoclast development (3, 4, 5, 6, 7, 8, 9). These cytokines stimulated osteoclast formation in cocultures of mouse osteoblastic cells and bone marrow cells (3, 4, 5). In addition, neutralizing antibody against gp130 more or less inhibited osteoclast formation induced by 1,25(OH)2D3, PTH, IL-1, and PGE2 in the same coculture system (5). These results indicate that gp130 is a crucial signal transducer for osteoclast development in vitro. Although the effects of cytokines belonging to the IL-6 family on bone resorption have also been examined in vitro in bone organ culture, these results are not consistent in each organ culture system. IL-6 (7), IL-11 (9), and LIF (10) stimulated bone resorption in calvarial organ culture, but LIF (11, 12) and OSM (8) inhibited bone resorption when long bones were used. Recent studies using transgenic mice and gene targeting have provided more detailed information about the roles of the IL-6 family of cytokines in bone resorption. IL-6-deficient mice generated by gene targeting exhibited no significant changes in osteoclast number compared with the wild-type mice (13), but overexpression of IL-6 in the transgenic mice induced a decrease in osteoclast number (14). OSM transgenic mice exhibited osteopetrotic bone, which might have been caused by stimulation of bone formation or inhibition of bone resorption (15). Targeted disruption of low-affinity LIF receptor (LIFR) induced an increase in osteoclast number compared with the wild-type mice and resulted in osteopenia (16). Thus, the role of IL-6 family cytokines in osteoclast formation and function is still controversial. This might be due to differences in assay systems and functional redundancy in IL-6 family cytokines.

Because the cytokines belonging to the IL-6 family share gp130 as a common signal transducer, this molecule may play a critical role in osteoclastogenesis induced by these cytokines. To explore the role of gp130 in osteoclastogenesis, we investigated bones in gp130-deficient mice generated by gene targeting. We report here that both bone marrow cavities and osteoclasts are present in gp130-deficient mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Mice deficient in gp130 with the genetic background of a mixture of 129 and C57BL/6 were generated by targeted disruption of the gene as described previously (17). These mice died between 12.5 days post coitus and term due to defects in multiple organs (17). Because it has been reported that some embryonic lethal mice generated by gene disruption could survive until birth by crossing with other strains of mice (18, 19), the original gp130-deficient mice were repeatedly crossed with mice of the ICR strain. Some of the mice developed to term but died shortly after birth with no milk in the stomach (K. Yoshida, T. Taga, T. Kishimoto, et al., unpublished observations). These gp130-deficient mice were smaller than the wild-type and heterozygous mice at birth. In the present study, we used these gp130-deficient mice just after birth. The morphological changes of bones were examined in five each of knockout and wild-type mice and two heterozygous mice. The extremities obtained from three each of gp130-deficient and wild-type mice were fixed for 3 days with neutral buffered 10% formalin at 4 C and washed with PBS. To investigate the distribution of alkaline phosphatase (ALP)-positive cells in the undecalcified sections, the lower extremities and heads isolated from the other two each of knockouts, wild-type, and heterozygous mice were also fixed for 12 h with neutral buffered 10% formalin at 4 C.

X-ray examination
Radiograms of the hind extremities were taken using soft x-rays (type SRO-M50, Sofron, Tokyo, Japan). To analyze the structure of the bone in more detail, we applied microfocus x-ray computed tomography (MFXDT) (20) (Nittetu Elex Co., Ltd., Osaka, Japan). Using this equipment, radii in the wild-type and gp130-deficient mice were scanned at 5-µm intervals along the longitudinal axis.

Histological examination
After taking soft x-ray radiograms, the hind extremities and skulls were dehydrated through a graded series of ethanol and embedded in plastic resin (JB-4; Polysciences, Warrington, PA). Serial undecalcified sagittal sections of tibiae and frontal sections of skulls were cut with a Reihert-Jung microtome (Model 2050 Supercut). These sections were used for dual staining with von Kossa and tartrate-resistant acid phosphatase (TRAP), a marker enzyme of osteoclasts. The sections were first stained using von Kossa’s method by incubation for 5 min with 0.5% silver nitrate in daylight, then excess staining was removed by incubation of the sections for 5 min with 0.5% sodium thiosulfate. After washing with PBS, the sections were stained for TRAP by incubation for 30 min with a mixture of 0.1 mg/ml naphthol AS-MX phosphate (Sigma Chemical Comp., St. Louis, MO), 0.5% N,N-dimethylformamide (Wako Pure Chemical Industries, Osaka, Japan), 0.5 mg/ml fast red AL salt (Sigma), and 50 mM sodium tartrate dehydrate (Wako) in 0.1 M acetate buffer solution (pH 5.0) at room temperature. The sections were counterstained with hematoxylin. TRAP-positive cells containing more than two nuclei were identified as osteoclasts in the stained sections. Some undecalcified sections were dual-stained for ALP (21) and von Kossa. The following bone histomorphometric parameters were measured in a rectangular area (0.31 x 0.62 mm) in the proximal tibia using bone histomorphometry software (System Supply, Nagano, Japan). This area was approximately 0.1 mm distal from the growth plate and endosteal surface. The parameters measured were trabecular bone volume (BV/TV, %; bone volume/tissue volume x 100) and osteoclast number (Oc.N.,/mm; number of TRAP-positive osteoclasts/bone surface). Osteoclast number in the cortical region was also measured separately from that in the metaphysial region. The results of bone histomorphometry are expressed as the means ± SE. The data were analyzed by one-way ANOVA, and the differences in the means were assessed using the Bonferroni/Dunn multiple comparison test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
X-ray findings
Soft x-ray examination revealed that the diaphyses of tibiae and fibulae in both wild-type and gp130-deficient mice were composed of well-calcified bones (Fig. 1Go). Radiolucent regions that suggest the presence of the bone marrow cavity were observed along the longitudinal axis of these bones in both wild-type and gp130-deficient mice (Fig. 1Go). Figure 2Go summarizes typical MFXCT images at the midportion of radii of the wild-type and the gp130-deficient mice when scanned along the longitudinal axis. They clearly showed the presence of bone marrow cavities in both wild-type and gp130-deficient mice. MFXCT images also revealed a decreased amount of trabeculae at the metaphysial region, thin cortical bones, and shortened diaphysis in gp130-deficient mice, compared with those in the wild-type mice (Fig. 2Go).



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  		Figure 1. Soft x-ray microradiograms of lower extremities in wild-type (A) and gp130-deficient (B) mice. After fixation of lower extremities, soft x-rays were taken as described in Materials and Methods.

 


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  		Figure 2. MFXCT images of radii in wild-type (A) and gp130-deficient (B) mice. After fixation of upper extremities, radii from wild-type and gp130-deficient mice were scanned at 5-mm intervals along longitudinal axis of bones. MFXCT images in each group represent typical features at 50-µm intervals.

 
Histological findings
Figure 3Go summarizes the features of the tibiae of three wild-type mice and three gp130-deficient mice. All three gp130-deficient mice had less trabecular bone at the metaphysial region, compared with the wild-type controls. This finding coincides well with that on the MFXCT images shown in Fig. 2Go. There were no apparent differences in the histology of cartilaginous epiphysis between the wild-type and the gp130-deficient mice. Figure 4Go shows a high-power view of the metaphysial regions of the proximal tibiae. In the wild-type mice, there were numerous mineralized spicules composed of the primary spongiosa directly extending from the calcified cartilage into the bone marrow cavity. Numerous mineralized trabecular bones with secondary spongiosa also extended from the primary spongiosa in these mice. In the gp130-deficient mice, however, the numbers of mineralized spicules composed of primary spongiosa were markedly decreased compared with the wild-type controls. Trabecular bone forming secondary spongiosa was scarcely observed in the gp130-deficient mice. TRAP-positive osteoclasts were detected on the surface of both trabecular bone and calcified cartilage at the metaphysial region in both wild-type and gp130-deficient mice. The number of osteoclasts in the gp130-deficient mice at the metaphysial region was greater than that in the wild-type controls (Fig. 4Go). The surface of trabecular bones was covered with ALP-positive osteoblasts and a thin osteoid layer in both gp130-deficient and wild-type mice. There were no apparent differences in the distribution of ALP-positive osteoblasts (Fig. 5Go) between the wild-type and the gp130-deficient mice. Histology of tibiae, including distribution of TRAP-positive cells and ALP-positive cells, in the heterozygous mice was almost identical to that in wild type mice (data not shown).



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  		Figure 3. Histological features of tibiae of three wild-type (A–C) and three gp130-deficient (D-F) mice. Sections were prepared and stained by TRAP and von Kossa’s method as described in Materials and Methods. Bones in A, B, D, and E were obtained from animals from same litter, and bones in C and F were from another litter. x15.

 


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  		Figure 4. Histology of metaphysial regions of wild-type (A) and gp130-deficient (B) mice. Sections were prepared and stained by TRAP and von Kossa’s method as described in Materials and Methods. Cells stained red represent TRAP-positive osteoclasts, and bone matrices stained brown represent mineralized bone. x100.

 


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  		Figure 5. Histology of metaphysial regions of wild-type (A) and gp130-deficient (B) mice. Sections were prepared and stained by ALP and von Kossa’s method as described in Materials and Methods. Cells stained blue represent ALP-positive cells, and bone matrices stained brown represent mineralized bone. x140.

 
To quantify the above histological findings, we measured bone volume and osteoclast number at the metaphysial region of the proximal tibia by conventional bone histomorphometry. Bone volume in the gp130-deficient mice was about one third of that in the wild-type controls (Fig. 6AGo). The osteoclast number at the metaphysial region of gp130-deficient mice was about double that in the wild-type controls (Fig. 6BGo). In the cortical region, the number of osteoclasts in the gp130-deficient mice was also higher than that in the wild-type controls, but this difference was not significant (Fig. 6BGo).



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  		Figure 6. Bone histomorphometric parameters in wild-type and gp130-deficient mice. Bone volume (BV/TV, %) (A) and osteoclast number (B) in metaphysial region of three wild-type and three gp130-deficient mice were analyzed as described in Materials and Methods. Osteoclast number in cortical region was also compared between wild-type and gp130-deficient mice (B). Data are means ± SE of three mice. *, P < 0.05 and **, P < 0.01 between wild-type (gp130+/+) and gp130-deficient (gp130-/-) mice.

 
To investigate the histological changes in bones other than tibiae, we compared the histology of mandibulae between the wild-type, heterozygous and gp130-deficient mice (Fig. 7Go). In both wild-type and heterozygous mice, the cortical region of the mandibulae consisted of well-mineralized bones, and numerous mineralized trabecular bones were observed within the mandibulae (Fig. 7Go, A–D). Many TRAP-positive osteoclasts were located on the surface of the mineralized bones in these mice (Fig. 7Go, A and C). Numerous ALP-positive cells were distributed at the periosteal region and between the trabecular bones (Fig. 7Go, B and D). In the gp130-deficient mice, mineralized bones were relatively well retained at the cortical region, but the amount of trabecular bones remaining inside the mandibulae (Fig. 7Go, E and F) was much less than in the wild-type and heterozygous mice (Fig. 7Go, A–D). Numerous TRAP-positive osteoclasts appeared within of the mandibulae in gp130-deficient mice (Fig. 7EGo). The number of TRAP-positive osteoclasts in gp130-deficient mice was greater than in the wild-type and heterozygous mice (Fig. 7Go, A and C vs. E). Numerous ALP-positive cells occupied the periosteal region and the bone marrow space in the gp130-deficient mice (Fig. 7FGo).



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  		Figure 7. Histology of mandibulae of wild-type (A and D), heterozygous (B and E) and gp130-deficient (C and F) mice. Sections in A, B, and C were prepared and stained by TRAP and von Kossa’s method as described in Materials and Methods. Cells stained red represent TRAP-positive osteoclasts, and bone matrices stained brown represent mineralized bone. Sections in D, E, and F were prepared and stained by ALP and von Kossa’s method as described in Materials and Methods. Cells stained blue represent ALP-positive cells, and bone matrices stained brown represent mineralized bone. x32.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
During the development of long bones in mammals, osteogenic cells and blood capillaries invade from the periosteal region into the midportion of the mineralized cartilage to form the bone marrow cavity. In this process, chondroclasts and osteoclasts resorb mineralized cartilage and bone, respectively. The results of the present study clearly indicated that the bone marrow cavity is also formed in long bones of gp130-deficient mice, which was confirmed by soft x-ray (Fig. 1Go), MFXCT (Fig. 2Go), and histological examination (Fig. 3Go). In addition, numerous TRAP-positive multinucleated osteoclasts were observed in long bones of gp130-deficient mice (Fig. 4Go). These observations suggest that the formation of osteoclasts is not solely dependent on gp130 signaling, at least during fetal development.

The osteoclast number at the metaphysial region of tibiae in the gp130-deficient mice was about double that in the wild-type controls. The number of osteoclasts in mandibulae of gp130-deficient mice was also greater than that in the wild-type and heterozygous mice. It is likely that the decreased amount of trabecular bone at the metaphysial region of tibiae and mandibulae in gp130-deficient mice was due to increased osteoclastic bone resorption in these mutant mice. The formation and function of osteoclasts are also regulated by other bone resorbing hormones and cytokines such as 1,25(OH)2D3, PTH, IL-1, PGE2, and TNF (2). The accelerated osteoclastic bone resorption in gp130-deficient mice might be caused by functional redundancy in such bone-resorbing hormones and cytokines. It is important to identify bone-resorbing hormones and cytokines that compensate for the gp130-deficient state in osteoclast formation. In the present study, however, it was impossible to identify such molecules because the mutant mice died 1 day after birth.

The histological bone changes in gp130-deficient mice were very similar to those in the low-affinity LIFR gene knockout mice (16). LIFR-deficient mice exhibited a 6-fold increase in the osteoclast number and 60% decrease in the trabecular bone volume at the metaphysial region of long bones, compared with those in the wild-type controls. Recently, Jay et al. (8) reported that OSM inhibited basal bone resorption, but did not inhibit resorption induced by PTH in mouse embryonic long bone culture. Similar inhibitory effects of LIF on bone resorption were also demonstrated by other investigators in embryonic long bone cultures (11, 12). These results raise another possibility to explain the increased number of osteoclasts in gp130-deficient mice; cytokines belonging to the IL-6 family may inhibit basal bone resorption in embryos, and the lack of the common signal transducer of these cytokines, gp130, may overcome this inhibitory effect. Recently, Kitamura et al. (14) demonstrated that IL-6 transgenic mice exhibited low bone turnover with decreased osteoclast number and bone formation rate. OSM transgenic mice also exhibited osteopetrotic bones (15). Bone changes in these two lines of transgenic mice support the possibility that cytokines belonging to the IL-6 family inhibit basal bone resorption.

The gp130-deficient mice used in the present study developed to term but died shortly after birth. These mice were smaller than the wild-type and heterozygous mice probably due to defects in multiple organs. In addition, the length of bones in the extremities in the mutant mice was shorter than that of wild-type controls. These observations suggested that increased osteoclast number was caused by the severely compromised general health of the mutant mice including hypocalcemia. The gp130-deficient mice had no milk in the stomach after birth. This might not be a major cause of the observed osteopenia in the mutant mice, because gp130-deficient embryos (18.5 dpc) also exhibited increased number of osteoclasts in tibiae compared with the wild-type controls (A. Y., unpublished observation). Further analysis of the pathological condition of the mutant mice is necessary to determine the role of gp130 in osteoclastogenesis in these animals.

It is important to examine the changes in bone formation in gp130-deficient mice because cells of osteoblast/bone marrow stromal cell lineage express receptors for various cytokines belonging to the IL-6 family such as IL-11, LIF, and OSM (22). In the present study, the distributions of ALP-positive cells on the trabecular bone surface in tibiae were similar between the wild-type and the gp130-deficient mice. In addition, numerous ALP-positive cells occupied the marrow space between the trabecular bones in the mandibulae of gp130-deficient mice. These results suggest that osteoblast function is not severely affected by the lack of gp130 in developing bones. The most reliable bone histomorphometric technique to assess bone formation in vivo is double labeling with tetracycline or calcein. Because the gp130-deficient mice died as early as 1 day after birth, such experiments could not be performed. The bone tissue of the gp130-deficient mice was composed mainly of immature woven bone. In addition, the gp130-deficient mice did not have sufficient secondary spongiosa, which is essential for the assessment of double labeling.

It has been reported that cytokines belonging to the IL-6 family play crucial roles in bone resorption in pathological conditions such as estrogen deficiency. Jilka et al. (6) demonstrated that the increase in osteoclast number due to estrogen deficiency was corrected by administration of anti-IL-6 antibody into ovariectomized mice, but the same treatment did not affect the osteoclast number in sham-operated controls. Poli et al. (13) reported that ovariectomy did not induce any changes in the osteoclast number or bone formation rate in IL-6-deficient mice, resulting in no reduction of bone volume. Interestingly, there were no significant differences in the osteoclast number between wild-type and IL-6-deficient mice before ovariectomy, suggesting that IL-6 is not essential for osteoclastic bone resorption in mice with intact ovarian function (13). Taken together, it is likely that the signal tansduction system through gp130 plays an important role in osteoclast development in pathological conditions such as estrogen deficiency rather than in normal development.


   Acknowledgments
 
We thank Dr. Naoyuki Takahashi for his helpful discussion, and also thank Mr. Atsushi Koishikawa and Mr. Hidekazu Hirai (Nittetsu Elex Co., Ltd.) for taking MFXCT images.


   Footnotes
 
1 Part of this study was presented at the 16th Japanese Congress on Bone Morphometry. Back

2 Awarded the Young Investigator Award of the Japanese Society of Bone Morphometry. Back

3 Present address: Department of Operative Dentistry, School of Dentistry, Meikai University, Saitama 350–02, Japan. Back

4 Present address: Department of Molecular Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101, Japan. Back

Received April 4, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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