Journal of Bone Metabolism (JBM) Added to the SCOPUS

No abstract available.

α-Tocopheryl Succinate Inhibits Osteolytic Bone Metastasis of Breast Cancer by Suppressing Migration of Cancer Cells and Receptor Activator of Nuclear Factor-κB Ligand Expression of Osteoblasts

BACKGROUND: Breast cancer is one of the most common cancers affecting women and has a high incidence of bone metastasis, causing osteolytic lesions. The elevated expression of receptor activator of nuclear factor-κB ligand (RANKL) in cancer activates osteoclasts, leading to bone destruction. We previously reported that α-tocopheryl succinate (αTP-suc) inhibited interleukin-1-induced RANKL expression in osteoblasts. Here, we examined the effect of αTP-suc on osteolytic bone metastasis in breast cancer. METHODS: To examine the effect of αTP-suc on the metastatic capacity of breast cancer, MDA-MB-231-FL cells were injected into the left cardiac ventricle of BALB/c nude mice along with intraperitoneal injection of αTP-suc. The mice were then analyzed by bioluminescence imaging. To investigate the effect of αTP-suc on osteolysis, 4T1 cells were directly injected into the femur of BALB/c mice along with intraperitoneal injection of αTP-suc. Microcomputed tomography analysis and histomorphometric analysis of the femora were performed. RESULTS: αTP-suc inhibited cell migration and cell growth of 4T1 cells. In line with these results, bone metastasis of MDA-MB-231-FL cells was reduced in mice injected with αTP-suc. In addition, αTP-suc decreased osteoclastogenesis by inhibiting 4T1-induced RANKL expression in osteoblasts. Consistent with these results, 4T1-induced bone destruction was ameliorated by αTP-suc, with in vivo analysis showing reduced tumor burden and osteoclast numbers. CONCLUSIONS: Our findings suggest that αTP-suc may be efficiently utilized to prevent and treat osteolytic bone metastasis of breast cancer with dual effects.

Stimulation of osteoclast migration and bone resorption by C–C chemokine ligands 19 and 21

Osteoclasts are responsible for the bone erosion associated with rheumatoid arthritis (RA). The upregulation of the chemokines CCL19 and CCL21 and their receptor CCR7 has been linked to RA pathogenesis. The purpose of this study was to evaluate the effects of CCL19 and CCL21 on osteoclasts and to reveal their underlying mechanisms. The expression of CCL19, CCL21 and CCR7 was higher in RA patients than in osteoarthritis patients. In differentiating osteoclasts, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide stimulated CCR7 expression. CCL19 and CCL21 promoted osteoclast migration and resorption activity. These effects were dependent on the presence of CCR7 and abolished by the inhibition of the Rho signaling pathway. CCL19 and CCL21 promoted bone resorption by osteoclasts in an in vivo mice calvarial model. These findings demonstrate for the first time that CCL19, CCL21 and CCR7 play important roles in bone destruction by increasing osteoclast migration and resorption activity. This study also suggests that the interaction of CCL19 and CCL21 with CCR7 is an effective strategic focus in developing therapeutics for alleviating inflammatory bone destruction.

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2. In this study, we observed that secretion of CXCL10 in the supernatant of 4T1 cells was gradually increased during cell growth. JN-2 inhibited basal and CXCL10-induced CXCL10 expression and cell motility in 4T1 cells. Treatment of 4T1 cells with CXCL10 increased the expression of P65, a subunit of the NF-κB pathway, via activation of the NF-κB transcriptional activity. Ectopic overexpression of P65 increased CXCL10 secretion and blunted JN-2-induced suppression of CXCL10 secretion, whereas overexpression of IκBα suppressed CXCL10 secretion. These results indicate that the CXCL10/CXCR3 axis creates a positive feedback loop through the canonical NF-κB signaling pathway in 4T1 cells. In addition, treatment of osteoblasts with conditioned medium from JN-2-treated 4T1 cells inhibited the expression of RANKL, a crucial cytokine for osteoclast differentiation, which resulted in an inhibitory effect on osteoclast differentiation in the co-culture system of bone marrow-derived macrophages and osteoblasts. Direct intrafemoral injection of 4T1 cells induced severe bone destruction; however, this effect was suppressed by the CXCR3 antagonist via downregulation of P65 expression in an animal model. Collectively, these results suggest that the CXCL10/CXCR3-mediated NF-κB signaling pathway plays a role in the control of autonomous regulation of CXCL10 and malignant tumor properties in breast cancer 4T1 cells.

A Novel Osteogenic Activity of Suberoylanilide Hydroxamic Acid is Synergized by BMP-2

BACKGROUND: Many histone deacetylase (HDAC) inhibitors are well recognized as potential anti-cancer drugs. Inhibition of HDACs induces temporal transcription or epigenetic control, thus regulating many different biological responses. Here, we investigated the osteogenic effect of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat). METHODS: The effects of SAHA on osteoblast differentiation were examined in the 6XOSE-Luc reporter assay for determination of runt-related transcription factor 2 (Runx2) activity and alkaline phosphatase (ALP) activity and in an immunoprecipitation assay to determine the Runx2 acetylation state. The osteogenic activity of SAHA in vivo was studied in and receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoporotic mouse model. RESULTS: SAHA increased the transcriptional activity of Runx2 in a dose-dependent manner in the 6XOSE-Luc reporter assay. SAHA by itself was unable to induce ALP activity; however, SAHA enhanced ALP activity induced by bone morphogenetic protein-2 (BMP-2). The degree of acetylation of Runx2 was increased with SAHA treatment, which suggests that the increase in Runx2 transcriptional activity might be dependent on stabilization by acetylation. Also, SAHA successfully reversed soluble RANKL-induced osteoporotic bone loss. CONCLUSIONS: Our study shows an intriguing osteogenic potential of SAHA in a BMP-2-dependent manner and suggests that SAHA could be used at lower doses along with BMP-2 to treat osteoporosis.

The Effects of a High Fat Diet Containing Diacylglycerol on Bone in C57BL/6J Mice

PURPOSE: In epidemiologic and animal studies, a high fat diet (HFD) has been shown to be associated with lower bone mineral density (BMD) and a higher risk of osteoporotic fractures. Meanwhile, consuming a HFD containing diacylglycerol (DAG) instead of triacylglycerol (TAG) is known to offer metabolically beneficial effects of reductions in body weight and abdominal fat. The purpose of this study was to investigate the effects of a HFD containing DAG (HFD-DAG) on bone in mice. MATERIALS AND METHODS: Four-week-old male C57BL/6J mice (n=39) were divided into three weight-matched groups based on diet type: a chow diet group, a HFD containing TAG (HFD-TAG) group, and a HFD-DAG group. After 20 weeks, body composition and bone microstructure were analyzed using dual energy X-ray absorptiometry and micro-computed tomography. Reverse transcription-polymerase chain reaction (PCR) and real-time PCR of bone marrow cells were performed to investigate the expressions of transcription factors for osteogenesis or adipogenesis. RESULTS: The HFD-DAG group exhibited lower body weight, higher BMD, and superior microstructural bone parameters, compared to the HFD-TAG group. The HFD-DAG group showed increased expression of Runx2 and decreased expression of PPARgamma in bone marrow cells, compared to the HFD-TAG group. The HFD-DAG group also had lower levels of plasma glucose, insulin, total cholesterol, and triglyceride than the HFD-TAG group. CONCLUSION: Compared to HFD-TAG, HFD-DAG showed beneficial effects on bone and bone metabolism in C57BL/6J mice.

Adseverin mediates RANKL-induced osteoclastogenesis by regulating NFATc1

Adseverin is a Ca2+-dependent actin filament-severing protein that has been reported to regulate exocytosis via rearrangements of the actin cytoskeleton in secretory cells. However, the role of adseverin in bone cells has not yet been well characterized. Here, we investigated the role of adseverin in osteoclastogenesis using primary osteoclast precursor cells. Adseverin expression was upregulated during RANKL (receptor activator of nuclear factor-kappaB ligand)-induced osteoclast differentiation. Moreover, genetic silencing of adseverin decreased the number of osteoclasts generated by RANKL. Adseverin knockdown also suppressed the RANKL-mediated induction of nuclear factor of activated T-cell c1 (NFATc1), which is a key transcription factor in osteoclastogenesis. In addition, adseverin knockdown impaired bone resorption and the secretion of bone-degrading enzymes from osteoclasts. These effects were accompanied by decreased NFATc1 expression and the activation of nuclear factor-kappaB. Collectively, our results indicate that adseverin has a crucial role in osteoclastogenesis by regulating NFATc1.

Inclusion in the PubMed Central database and increasing publication frequency

No abstract available.

alpha-Tocopheryl Succinate Inhibits Osteoclast Formation by Suppressing Receptor Activator of Nuclear Factor-kappaB Ligand (RANKL) Expression and Bone Resorption

OBJECTIVE: Osteoclasts are bone-resorbing multinucleated cells derived from the monocyte/macrophage lineage during normal and pathological bone turnover. Recently, several studies revealed that alpha-tocopheryl succinate (alphaTP-suc) have demonstrated potent anti-cancer activities in vitro and in vivo. However, the effects of alphaTP-suc on osteoclast formation and bone resorption remain unknown. Thus, in this study, we examined the effects of alphaTP-suc on osteoclast differentiation and bone resorbing activity in inflammatory bone loss model. METHODS: Osteoclast differentiation assay was performed by cocultures of mouse bone marrow cells and calvarial osteoblasts in culture media including interleukin-1 (IL-1). Osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP). The level of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ICR mice were administered an intraperitoneal injections of alphaTP-suc or dimethyl sulfoxide (DMSO) 1 day before the implantation of a freeze-dried collagen sponge loaded with phosphate-buffered saline (PBS) or IL-1 over the calvariae and every other day for 7 days. The whole calvariae were obtained and analyzed by micro-computed tomography (CT) scanning, and stained for TRAP. RESULTS: alphaTP-suc inhibits osteoclast formation in cocultures stimulated by IL-1 and decreased the level of expression of RANKL mRNA in osteoblasts. In addition, administered intraperitoneal injections of alphaTP-suc prevented IL-1-mediated osteoclast formation and bone loss in vivo. CONCLUSION: Our findings suggest that alphaTP-suc may have therapeutic value for treating and preventing bone-resorptive diseases, such as osteoporosis.

Tanshinone IIA inhibits osteoclast differentiation through down-regulation of c-Fos and NFATc1

Bone is a dynamic tissue that is regulated by the activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Excessive osteoclast formation causes diseases such as osteoporosis and rheumatoid arthritis. Natural substances may be useful as therapeutic drugs to prevent many diseases in humans because they avoid the many side effects of treatment with chemical compounds. Here we show that tanshinone IIA isolated from Salvia miltiorrhiza Bunge inhibits the receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast differentiation of osteoclast precursors. Tanshinone IIA suppressed the expression levels of c-Fos and NFATc1 induced by RANKL. However, retrovirus-mediated overexpression of c-Fos induced the expression of NFATc1 despite the presence of tanshinone IIA and reversed the inhibitory effect of tanshinone IIA on osteoclast differentiation. Also, the introduction of osteoclast precursors with the NFATc1 retrovirus led to osteoclast differentiation in the presence of tanshinone IIA. Our results suggest that tanshinone IIA may have a role as a therapeutic drug in the treatment of bone disease such as osteoporosis.

Lipid rafts are important for the association of RANK and TRAF6

Rafts, cholesterol- and sphingolipid-rich membrane microdomains, have been shown to play an important role in immune cell activation. More recently rafts were implicated in the signal transduction by members of the TNF receptor (TNFR) family. In this study, we provide evidences that the raft microdomain has a crucial role in RANK (receptor activator of NF-kappaB) signaling. We found that the majority of the ectopically expressed RANK and substantial portion of endogenous TRAF2 and TRAF6 were detected in the low-density raft fractions. In addition, TRAF6 association with rafts was increased by RANKL stimulation. The disruption of rafts blocked the TRAF6 translocation by RANK ligand and impeded the interaction between RANK and TRAF6. Our observations demonstrate that proper RANK signaling requires the function of raft membrane microdomains.

Development of bone regenerating material using bone morphogenetic protein(rhBMP-2) and bioresorbable polymer

A study of gingival blood flow using laser Doppler flowmetry / 대한치주과학회지

The periodontal health has been evaluated clinically by various epidemiological indices, and in researches by measurement of gingival crevicular fluid. Laser Doppler flowmetry is a reliable and objective method that allows immediate measurement of erythrocyte flux in approximately one cubic mm of the capillary bed without disturbing the tissues. The purpose of the present study was to determine whether human gingival blood flow was different according to measuring area, measuring time, and sex or not. Forty volunteers with good general and periodontal health, aged early twenties and unmarried, were selected. Laser Doppler flowmetry(floLAB(R), Moor Instruments Ltd., England) was applied to measure the gingival blood flow of marginal gingiva, interdental papilla, attached gingiva and alveolar mucosa. The blood flow of interdental papilla was measured at 9-10 AM, 1-2 PM, and 5-6 PM. The difference of blood flow according to measuring area and measuring time was statistically analyzed by one way ANOVA and Dunkan test, and the difference of blood flow between men and women was statistically analyzed by t-test. (1) Mean blood flow was significantly higher in alveolar mucosa than in the gingiva(p0.1). (2) Mean blood flow was significantly higher at 5-6 PM than at 9-10 AM and 1-2 PM(p0.1). (3) There was no significant difference in gingival blood flow between men and women(p>0.1). The above results suggest that the measurment of gingival blood flow using laser Doppler flowmetry may be clinically applicable to early determination of gingival inflammation and evaluation of healing status, but further studies are necessary to standardize and simplify the measuring procedure.

In vitro growth of candida albicans on several resilient dinture liners / 대한치과보철학회지

No abstract available.

Determination of antifungal ability of denture cleansing agents to candida albicans / 대한치과보철학회지

No abstract available.

A study on the level of the salivary oral microorganisms in fixed orthodontic patient / 대한치과교정학회지

This study was done to evaluate the effect of fixed orthodontic patients on the level of oral streptococci, Streptococcus mutans, lactobacilli, yeasts in saliva. 35 patients wearing bands were compared with age-matched 35 non-banded control group by colony counting method on the specially designed culture medium. The following results were obtained; 1. The colony forming unit(CFU) of total streptocci per militer of saliva in subjects with or without orthodontic treatment showed no significant statistical difference between them(p>0.05). 2. The colony forming unit(CFU) of total Streptococcus mutans per mililiter of saliva in subjects with orthodontics treatment showed significantly higher than those without orthodontic treatment(p0.05).