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The fixed herbal drug composition "Saikokaryukotsuboreito" prevents bone loss with an association of serum IL-6 reductions in ovariectomized mice model.


Purpose: Saikokaryukotsuboreito (SRB) is a traditional Japanese herbal medicine that has been used to treat hyperlipidemia. As some studies have shown that lipid-lowering drugs reduce osteoporosis, we investigated the effect of SRB on bone metabolism in the postmenopausal period using an ovariectomized (OVX) murine model.

Material and Methods: Fifteen aged 9 weeks female mice were divided into three groups (n = 5 each). The OVX group and SRB group underwent bilateral ovariectomy, after which the OVX group was fed a normal diet and the SRB group fed a normal diet containing 2% SRB. The sham group underwent sham surgery and was then fed a normal diet. Eight weeks after surgery, all mice were sacrificed, and bone volume, bone histomorphometric parameters, and bone-associated phenotype were compared among the groups.

Results: Compared with the OVX group, the SRB group showed suppression of bone volume loss at the tibia (SRB group: 12.7 [+ or -] 0.7%, OVX group: 9.8 [+ or -] 0.4%; p = 0.005, ANOVA) and lumbar spine (SRB group: 15.1 [+ or -] 0.9%, OVX group: 11.3 [+ or -] 0.1%; p=0.031, ANOVA). A significant decrease in eroded surface was also observed in SRB-treated ovariectomized mice compared with the OVX group (p = 0.022, ANOVA). We also found that serum levels of interleukin (IL)-6, a primary mediator of bone resorption, in the SRB group were significantly lower than in the OVX group (SRB: 52.5 [+ or -] 6.8 pg/ml; OVX: 138.0 [+ or -] 23.1 pg/ml; p = 0.011, ANOVA). However, unexpectedly, SRB did not affect estradiol and total cholesterol in ovariectomized mice.

Conclusion: SRB can prevent loss of bone volume and suppress serum IL-6 levels in this postmenopausal model and is a promising candidate for treatment of postmenopausal osteoporosis.

[C] 2010 Elsevier GmbH. All rights reserved.


Keywords: Saikokaryukotsuboreito Osteoporosis IL-6 Herbal medicine


Postmenopausal osteoporosis is one of the natural consequences of aging (Riggs and Melton, 1995). It is a skeletal disorder characterized by progressive loss of bone tissue and deterioration of osseous microarchitecture which begins after natural or surgical menopause and results in an increased risk of fracture (Hodsman, 2001). Melton et al. (1989) reported that 25% of women aged 80-84 years have had at least one vertebral fracture. Fractures can reduce mobility and be very painful, thereby limiting everyday activities (Hill, 1996).

Epidemiological evidence has accumulated indicating that osteoporosis and hyperlipidemia frequently coexist, suggesting a link between bone and lipid metabolism (Ray et al., 2002). Several studies have shown that statins, which are known to have lipid-lowering effects, also have potentially beneficial effects on bone metabolism (Edwards et al., 2000; Mundy et al., 1999).

Saikokaryukotsuboreito (SRB) (Tsumura Co., Tokyo, Japan) is a traditional Japanese herbal medicine that has been used to decrease serum triglycerides and inhibit aortic intimal thickening in hypertension (Yamada et al., 1998).

This study investigated the effects of SRB on bone morphology and substances associated with bone metabolism in the postmenopausal period using an ovariectomized mouse model.

Materials and methods

Preparation of SRB extract, three-dimensional HPLC analysis and liquid chromatography-mass spectrometry (LC-MS/MS)

The SRB extract used was manufactured by Tsumura & Co. (Tokyo, Japan). It is composed of 10 crude drugs in fixed proportions: 5.0 g of Bupleurum Root (the root of Bupleurum falcatum Linne), 4.0 g of Pinelliae Tuber (the tuber of Pinellia ternate Breitenbach), 3.0 g of Cinnamon Bark (the bark of Cinnamomum cassia Blume), 3.0 g of Poria Sclerotium (the sclerotium of Poria cocos Wolf). 2.5 g of Scutellariae Root (the root of Scutellaria baicalensis Georgi), 2.5 g of Jujube (the fruit of Zizyphus jujube Miller var. inermis Rehder), 2.5 g of Ginseng (the root of Panax ginseng C. A. Meyer), 2.5 g of Ostreae Shell (the shell of Ostrea gigas Thunberg), 2.5 g of Longgu (the Fossilia ossis mastodi, mainly comprising calcium carbonate), and 1.0 g of Ginger (the rhizome of Zingiber officinal Roscoe). These crude drugs were decocted in a 10-fold volume of water for 60 min, filtered, and the filtrate spray-dried to obtain an extract yield of about 10% by weight of the original preparation. For the analysis of SRB components, the aqueous extract (0.5 g) was extracted with 20 ml of methanol under ultrasonication for 30 min. The solution was filtered through a membrane filter (0.45 [micro]n) then subjected to high-performance liquid chromatography (HPLC) analysis. The HPLC apparatus consisted of a Shimadzu LC 10A (analysis system software: CLASS-M10A ver. 1.64, Tokyo, Japan) equipped with a multiple wavelength detector (UV 200-400 nm) (Shimadzu SPD-M10AVP, diode array detector) and an auto injector (Shimadzu CTO-10AC). HPLC conditions were as follows: column, ODS (TSK-GEL 80TS, 250 x 4.6 mm i.d., TOSOH, Tokyo, Japan); eluant, (A) 0.05 M AcO[NH.sub.4] (pH 3.6), (B) 100% [CH.sub.3]CN; linear gradient of 90% A and 10% B changing to 0% A and 100% B in 60 min (100% B was continued for 20 min); temperature, 40 [degrees]C; flow rate, 1.0 ml/min. The HPLC profile of SRB extract is shown in Fig. 1. Baicalin, baicalein, oroxylin-A and wogonin were detected as the major compounds of SRB, while cinnamic acid, saikosaponin, gingerol, and cinnamaldehyde were also observed. However, we could not detect ginsenoside, pachymic acid and beturinic acid in this HPLC analysis. Thus, we performed LC-MS/ MS analysis (Fig. 2A) of Fr.l using a system with the 1100 Agilent auto sampler, HPLC instrument (Agilent Technologies, Inc. Tokyo, Japan), and API 2000 mass spectrometer (Applied Biosystems/MDS Sciex, Tokyo, Japan). Chromatography was carried out on a reversed-phase YMC Pack ODS-AQ. column (50 x 2.0 mm i.d.) with the mobile phase consisting of solvent A (10 mM ammonium formate) and solvent B (acetonitrile). A 22-min gradient was established running from 23% to 35% B over the first 4 min, 35% to 90% B over the following 5 min, and 90% B over the last 3 min before returning the system to its initial 23% B at 10 min. For qualification, Fr.1 was prepared in methanol, filtered, and transferred to the auto sampler for LC-MS/MS analysis. Standards were prepared in a mixture of methanol, 10 mM ammonium formate and acetonitrile (3:3:2). Standards and Fr.1 were injected (10 [micro]1) into the LC-MS/MS system.



The column effluent was introduced into the mass spectrometer using electrospray ionization (ESI) in the positive and negative ion modes with nitrogen as the nebulizer and curtain gas. In the positive ion mode, the nebulizer current and temperature were 40 psi and 450 [degrees]C, respectively. The collision gas ([N.sub.2]) was set at 5 psi and collision energy was 17 eV (pachymic acid), 29 eV (ginsenoside Rg1), 29 eV (ginsenoside Rf), 35 eV (ginsenoside Re), 43 eV (ginsenoside Rc), 47 eV (ginsenoside Rb1), and 43 eV (ginsenoside Rb2) with an electron multiplier voltage of 5500 V. Ginsenoside analog ions were detected as ammonium adducts [M + NH4+] +. In the negative ion mode, the nebulizer current and temperature were 20 psi and 450 [degrees]C, respectively. The collision gas ([N.sub.2]) was set at 2 psi and collision energy was -24 eV (beturinic acid) with an electron multiplier voltage of -4200 V. Betulinic acid ion was detected as formate adducts [M + HCOO-]-.The following mass transitions were used for MRM analysis: pachymic acid m/z = 529/511, ginsenoside Rg1 m/z = 818/423, ginsenoside Rf m/z = 818/423, ginsenoside Re m/z = 965/423, ginsenoside Re m/z = 1097/325, ginsenoside Rbl m/z-1127/325, ginsenoside Rb2 m/z = 1097/325 (positive ion mode), and betulinic acid m/z = 501/455 (negative ion mode) (Fig. 2B and C). The LC-MS/MS system was controlled by BioAnalyst 1.4.1 software.

SRB preparation and animals

Spray-dried, water-extracted SRB powder was obtained from Tsumura & Co. C57BL/6N female mice, aged 8 weeks, were purchased from Japan Oriental Yeast Co. (Tokyo, Japan). All mice were housed under specific pathogen-free conditions with a 12 h light/dark cycle. The housing care rules and experimental protocol were approved by the Animal Care and Use Committee of Osaka University.

At the age of 9 weeks, these mice, with an average body weight 19.8 g (19.8 [+ or -] 0.3 g), were randomly divided into three groups. The first group (OVX group, n = 5) and the second group (SRB group, n = 5) were anesthetized with intraperitoneal injection of pentobarbital (Dainippon Sumitomo Pharma, Osaka, Japan) and bilaterally ovariectomized. For 8 weeks after surgery, the OVX group was fed a normal diet (powdered MF, Oriental Yeast Co., Ltd) and the SRB group was fed a normal diet containing 2% SRB. The last group (sham group, n = 5) was sham-operated and fed a normal diet for 8 weeks after surgery. General condition, food intake, and body weight were recorded for all mice.

Micro-computed tomography (CT)

Eight weeks after surgery, at 17 weeks old, all mice were sacrificed. The tibia from each animal was sampled and the soft tissue cleaned off. The proximal metaphysis of the tibia was then scanned with a Micro-CT system (SMX-100CT-SV; Shimadzu, Kyoto, Japan) in 600 slices at a tube voltage of 45 kV and tube current of 75 [micro]A, and the trabecular bone area (percentage of bone volume [BV] per tissue volume [TV]) was measured.

Bone histomorphometry

All mice were injected subcutaneously with 16 mg/kg calcein 7 and 2 days before being sacrificed. The lumbar spine was removed and fixed with 70% ethanol, dehydrated, and embedded in glycolmethacrylate (GMA) resin. The region studied was the secondary spongiosa, excluding the primary spongiosa 0.2 mm distal from the growth plate. Static and dynamic bone histomor-phometric measurements of trabecular bone area were performed. Bone histomorphometric parameters were measured as described in the report of The American Society for Bone and Mineral Research (ASBMR) Histomorphometry Nomenclature Committee (Perfitt et al., 1987).

Serum analysis

Immediately after sacrifice, blood was withdrawn from the abdominal aorta. Serum estradiol and interleukin (IL)-6 levels were measured using an enzyme-linked immunoassay kit (estradiol: Cayman Chemical, Ann Arbor, MI, USA; IL-6: Bender Medsystems, Vienna, Austria). Total cholesterol was measured using a Wako L-type CHO H kit (Wako Pure Chemical Industries, Osaka, Japan). Sensitivities of these assays were as follows: estradiol, 20 pg/ml; total cholesterol, 0.4 mg/dl; IL-6, 12 pg/ml.

Statistical analysis

All data are expressed as the mean [+ or -] standard error of the mean (SEM). Statistical analysis was performed using JMP IN 5.1 (SAS Institute, Cary, NC, USA). Statistical significance of comparisons was determined by one-way analysis of variance (ANOVA). Values of p < 0.05 were considered to indicate statistical significance.


SRB had no adverse effects

All mice survived after ovariectomy or sham operation. No mice in the SRB group experienced side effects, including weight loss or unusual activity. There was no significant difference in food intake per day among the three groups (OVX: 4.1 [+ or -] 1.1 g; SRB: 4.0 [+ or -] 0.8 g; sham: 3.5 [+ or -] 0.3 g; one-way ANOVA, p = 0.16). There was also no significant difference in body weight among the three groups (OVX: 29.8 [+ or -] 0.4 g; SRB: 29.5[+ or -] 0.8 g; sham: 28.1 [+ or -] 0.5 g; one-way ANOVA, p = 0.14) at the end of the experiment.

SRB suppressed loss of tibial trabecular bone volume in ovariectomized mice

To investigate the role of SRB in bone metabolism, we determined structural changes in trabecular bone with micro-CT. Fig. 3A-C show representative micro-CT images of the proximal tibia of the three groups, indicating deterioration of the microarchitecture in the OVX group compared with the SRB group. Fig. 3D shows that trabecular bone volume in the SRB group was significantly greater than in the OVX group (OVX group: 9.8 [+ or -] 0.4%; SRB group: 12.7 [+ or -] 0.7%; sham group: 17.2 [+ or -] 1.2% one-way ANOVA, p = 0.0001). Although the differences between the SRB and sham group were statistically significant, bone volume in the SRB group tend to be maintained closer to levels in the sham group compared with the OVX group.


SRB suppressed loss of trabecular bone volume of lumbar vertebrae in ovariectomized mice

Bone histomorphometric parameters at the end of the experiment are shown in Fig. 4. Bone volume of the lumbar vertebrae was significantly larger in the SRB group than in the OVX group (one-way ANOVA, p = 0.0015, Fig. 4A). Bone volume in the SRB group did not differ significantly from that in the sham group. Trabecular bone number (Tb.N) and trabecular bone space (Tb.Sp) in the SRB group were closer to sham group readings than those in the OVX group, although the differences between the SRB and sham group were statistically significant (Tb.N, one-way ANOVA, p = 0.0014; Tb.Sp, p = 0.0008; Fig. 4C and D).

The ratios of osteoblast surface (Ob.S)/bone surface (BS) and osteoclast surface (Oc.S)/BS in the SRB group tended to be smaller than those in the OVX group, but there were no significant differences between these two groups (Ob.S/BS: one-way ANOVA, p = 0.81; Oc.S/BS: p = 0.29; Fig. 4E and H).

The eroded surface (ES)/BS (%) was significantly smaller in the SRB group than in the OVX group (one-way ANOVA, p = 0.054, Fig. 4F). No significant difference was observed between the SRB and OVX groups for mineral apposition rate (MAR) or bone formation rate (BFR) (Fig. 41 and K).

SRB downregulated serum IL-6 level in ovariectomized mice

Next, we examined the effect of SRB on serum levels of estradiol, total cholesterol, and IL-6, because these are relevant to bone metabolism and change drastically in the perimenopausal period. Serum estradiol level was significantly higher in the sham group than in either the OVX or SRB groups (OVX: 9.5 [+ or -] 0.6 pg/ml; SRB: 8.7 [+ or -] 0.6 pg/ml; sham: 33.7 [+ or -] 3.9 pg/ml; one-way ANOVA, p < 0.0001). However, there was no significant difference in serum estradiol levels between the SRB and OVX groups. Total cholesterol was significantly lower in the sham group than in either the OVX or SRB groups, and, unexpectedly, cholesterol level was not suppressed in the SRB group (OVX: 87.5 [+ or -] 5.2 mg/ml; SRB: 85.3 [+ or -] 4.3 mg/ml; sham: 70.6 [+ or -] 7.4 mg/ml; one-way ANOVA, p = 0.01). Serum IL-6 levels were significantly lower in the SRB and sham groups than in the OVX group; IL-6 level did not increase in the SRB group despite ovariectomy (OVX: 138.0 [+ or -] 23.1 pg/ml; SRB: 52.5 [+ or -] 6.8 pg/ml; sham: 99.7 [+ or -] 19.3 pg/ml; one-way ANOVA, p = 0.02).


Estrogen deficiency in postmenopausal women results in enhanced bone resorption that leads to osteoporosis. For treatment and prevention of osteoporosis, raloxifene and the bisphosphonates are currently the preferred therapy. These agents effectively decrease bone resorption and increase bone mineral density, and reduce the risk of vertebral and other fractures (Delmas et al., 1997; Poole and Compston, 2007); however, they are associated with an increase in the incidence of fatal stroke, venous thromboembolic events (Barrett-Connor et al., 2006), osteonecrosis of the jaw, and gastrointestinal side effects (Ruggiero et al., 2004; Turbi et al., 2004). Hence, further therapeutic options for osteoporosis are needed.

In recent years, various Kampo medicines have been studied for their preventive effects on osteoporosis. Hachimijiogan, Juzentaihoto and Unkeito can improve ovarian function, so these three formulae were indicated to be useful for preventing postmenopausal osteoporosis (Hidaka et al., 1997; Okamoto et al., 1998; Chen et al., 2005). Yao et al. also reported that Goshajinkigan reduced trabecular bone loss as assessed by micro-CT in ovariectomized rats (Yao et al., 2007). Hidaka's group measured bone mineral density (BMD) and performed scanning electron micrography (SEM) in rats with osteoporosis and reported that Chujoto had similar efficacy to 17[beta]-oestradiol in treatment (Hidaka et al., 1999). Dae-bo-won-chun is also reportedly effective in preventing bone loss, and it suppresses the mechanical weakening of the femoral neck in ovariectomized rats (Chae et al., 2001). In addition, several in vitro studies have clarified how Kampo medicines work on bone metabolism (Li et al., 1998; Li et al., 1999; Shi et al., 2006). These studies indicate that several Kampo medicines can prevent osteoporosis.

Some studies have shown that lipid-lowering drugs reduce osteoporosis (Edwards et al., 2000; Mundy et al., 1999; Wang et al., 2000). Since SRB was reported to have an effect on hyperlipidemia (Yamada et al., 1998), we herein tested the hypothesis that SRB reduces bone loss in a postmenopausal model.

Using micro-CT, we showed that bone volume of the proximal tibia of SRB-treated mice was significantly greater than that of mice in the OVX group. Bone histomorphometric analysis of lumbar vertebrae also showed that SRB prevented the ovariectomy-induced loss of bone volume. In the SRB group, restoration of bone mass was more prominent for the spine than for the tibia. This finding was supported by previous studies, which revealed that bone loss in OVX rats was more rapid at appendicular bone sites (e.g., the tibia) than at axial bone sites (e.g., the lumbar vertebra) (Cui et al., 2004; Ke et al., 1995). A significant decrease in eroded surface and trends toward decreased osteoblast and osteoclast surfaces were also observed in SRB-treated ovariectomized mice compared with mice that underwent ovariectomy alone. These findings imply that SRB suppressed the rapid increase in bone turnover after ovariectomy. Bone formation indices such as MAR and BFR were not altered by SRB in ovariectomized mice. Taken together, these findings suggest that the protective effects of SRB on bone in ovariectomized mice are likely due to a suppression of bone resorption.

Unkeito, another Kampo medicine, has an estrogen-like effect and prevents the development of bone loss induced by ovariectomy in rats (Chen et al., 2005). However, the present study showed that SRB did not alter serum estradiol in ovariectomized mice. Although SRB and the extracts of Zingiber officinale and Cinnamomum cassia have previously been reported to have beneficial effects against hyperlipidemia, SRB did not affect serum total cholesterol level in the present study. This indicates that SRB could decrease serum total cholesterol level in a hyperlipidemia model (Chung et al., 2003; Yoshie et al., 2001) or in vitro (Kannappan et al., 2006; Matsuda et al., 2009), but not in an ovariectomy model.

Several reports show that IL-6 and other cytokines mediate bone loss induced by estrogen deficiency (Jika et al., 1992; Poli et al, 1994). In the presence of estrogen, IL-6 expression is suppressed, but its level increases in the absence of estrogen, and several clinical studies have shown high serum IL-6 levels among postmenopausal women (Pacifici et al., 1991). IL-6 is suggested to be a primary mediator of bone resorption through induction of osteoclastogenesis (Flanagan et al., 1995). IL-6 upregulation has an important role in the development of osteoporosis in ovariectomized mice and can be inhibited by androgen or IL-6 neutralizing antibody (Bellido et al., 1995). The present study showed that serum IL-6 levels in the SRB group were significantly lower than in the OVX group, suggesting that SRB can decrease serum IL-6 levels in this postmenopausal model.

Our histomorphometric results showed that the eroded surface (an indicator of osteoclast activity) was significantly smaller in the SRB group than in the OVX group. This lends support to the premise that SRB suppressed osteoclastogenesis by reducing serum IL-6 level. In our study, ovariectomized mice were not administered other therapies such as replacement estrogen therapy, which would have increased bone density and decreased serum IL-6. In that sense, we did not use any positive controls in this experiment. However, the comparison of bone and serum data with the OVX group support the idea that administration of SRB in a postmenopausal-osteoporosis model had an effect on preventing loss of bone volume and suppressing serum IL-6 levels.

Expression of IL-6 is largely controlled by nuclear factor-KB (NF[kappa]B) (Libermann and Baltimore, 1990). NF[kappa]B is an inducible dimeric transcription factor that belongs to the Rel/NF[kappa]B family of transcription factors. In resting cells, NF[kappa]B is sequestered in the cytoplasm by I[kappa]B proteins. Stimulus-mediated phosphorylation and subsequent proteolytic degradation of I[kappa]B allows the release and nuclear translocation of NF[kappa]B, where it transactivates a number of target genes. Recently, it was reported that saikosa-ponin, a principal component of SRB, inhibited T cell activation via the suppression of NF[kappa]B (Leung et al., 2005). Dang et al. (2007) reported that saikosaponin attenuated [CCl.sub.4]-induced hepatic fibrosis via downregulation of TNF[alpha], IL-6, and NF[kappa]B expression. Thus, one of the mechanisms by which SRB prevents the development of bone loss might be suppression of the expression of IL-6 via NF[kappa]B inactivation. Extracts of Cinnamomum cassia. Zingiber officinale and Panax ginseng, which represent the principal components of SRB, reportedly suppress osteoclastogenesis (Han et al., 2007; Liu et al., 2009; Sung et al., 2009; Tsuji-Naito, 2008). Incorporating these herbal medicines would thus also contribute to the prevention of bone loss.


We showed that SRB can prevent loss of bone volume and suppress serum IL-6 level in a postmenopausal model. Our results suggest that SRB deserves further investigation as a therapeutic option for treatment of postmenopausal osteoporosis.


We would like to thank Drs. Masafumi Kashii and Junko Murai for their helpful advice on the OVX experiment, and Yasuo Tsukamoto, Yousuke Hashimoto, Akitoshi Asami and Naoko Hattori for their excellent pharmacological advice.


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T. Hattori (a), *, W. Fei (b), T. Kizawa (a), S. Nishida (b), H. Yoshikawa (a), Y. Kishida (b)

(a) Department of Orthopaedics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

(b) Department of Kampo Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

* This study was supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (# 19791029 [Y. K.]).

* Corresponding author. Tel.: +81 06 6879 3552; fax: +81 06 6879 3559.

E-mail address: (T. Hattori).

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doi: 10.1016/j.phymed.2009.12.004
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Title Annotation:interleukin
Author:Hattori, T.; Fei, W.; Kizawa, T.; Nishida, S.; Yoshikawa, H.; Kishida, Y.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9JAPA
Date:Mar 1, 2010
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