Shin-Yoon Kim

Kyungpook National University Hospital, Sŏul, Seoul, South Korea

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Publications (136)380.81 Total impact

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    ABSTRACT: We examined the effects of triptolide on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and on titanium (Ti) particle-induced osteolysis. To examine the effect of triptolide on osteoclast differentiation, bone marrow macrophages (BMMs) were treated with 100 ng/mL of RANKL and 30 ng/mL of macrophage-colony stimulating factor, or co-cultured with osteoblasts stimulated with 10 nM vitamin D3 and 1 μM prostaglandin E2 in the presence or absence of triptolide (2.8-14 nM). Osteoclast differentiation and activation were assessed using tartrate-resistant acid phosphatase staining, reverse transcriptase-polymerase chain reaction analysis to determine differentiation marker gene expression and pit formation assays. To examine the effect of triptolide on wear debris-induced osteolysis, titanium (Ti) particles were injected into the calvaria of ICR mice. Then, the mice were divided into three groups and were orally administered vehicle, or 16 or 32 μg/kg/day triptolide for ten days, followed by histomorphometric analysis. Triptolide suppressed RANKL-mediated osteoclast differentiation of BMMs in a dose-dependent manner. In a co-culture system, osteoblasts treated with triptolide could not induce osteoclast differentiation of BMMs, which was accompanied by down-regulation of RANKL and up-regulation of osteoprotegrin. Moreover, triptolide significantly inhibited bone resorption, and expression of the bone resorption marker genes. RANKL-induced activation of p38, ERK, and JNK was substantially inhibited by triptolide. Further, in a Ti-induced mouse calvarial erosion model, mice perorally administrated with triptolide showed significant attenuation of Ti-mediated osteolysis. Our data indicated that triptolide had an anti-osteoclastic effect and significantly suppressed wear debris-induced osteolysis in mice.
    International Orthopaedics 11/2014; · 2.32 Impact Factor
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    ABSTRACT: Osteoclasts are large polykaryons that have the unique capacity to degrade bone and are generated by the differentiation of myeloid lineage progenitors. To identify the genes involved in osteoclast development, we performed microarray analysis, and we found that carboxypeptidase E (CPE), a prohormone processing enzyme, was highly upregulated in osteoclasts compared with their precursors, bone marrow-derived macrophages (BMMs). Here, we demonstrate a novel role for CPE in receptor activator of NF-kaapB ligand (RANKL)-induced osteoclast differentiation. The overexpression of CPE in BMMs increases the formation of tartrate- resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are key regulators in osteoclastogenesis. Furthermore, employing CPE knockout mice, we show that CPE deficiency attenuates osteoclast formation. Together, our data suggest that CPE might be an important modulator of RANKL-induced osteoclast differentiation.
    Molecules and cells. 09/2014;
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    ABSTRACT: Fatty acids, important components of a normal diet, have been reported to play a role in bone metabolism. Osteoclasts are bone-resorbing cells that are responsible for many bone-destructive diseases such as osteoporosis. In this study, we investigated the impact of a medium-chain fatty acid, capric acid, on the osteoclast differentiation, function, and survival induced by receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (MCSF). Capric acid inhibited RANKL-mediated osteoclastogenesis in bone marrow-derived macrophages and suppressed RANKL-induced IkappaBalpha phosphorylation, p65 nuclear translocation, and NF-kappaB transcriptional activity. Capric acid further blocked the RANKL-stimulated activation of ERK without affecting JNK or p38. The induction of NFATc1 in response to RANKL was also attenuated by capric acid. In addition, capric acid abrogated M-CSF and RANKLmediated cytoskeleton reorganization, which is crucial for the efficient bone resorption of osteoclasts. Capric acid also increased apoptosis in mature osteoclasts through the induction of Bim expression and the suppression of ERK activation by M-CSF. Together, our results reveal that capric acid has inhibitory effects on osteoclast development. We therefore suggest that capric acid may have potential therapeutic implications for the treatment of bone resorption-associated disorders.
    Molecules and cells. 08/2014;
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    ABSTRACT: Context: Osteoporotic fracture risk (OF) is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. Objective: To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. Design and setting: This cross-sectional study was conducted in three clinical units in Korea. Participants: Postmenopausal women with extreme phenotypes (n=982) were used for the discovery set and 3,895 participants were used for the replication set. Main Outcome Measure: We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. Results: Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%, P<0.001) and was further improved by adding GRS-T (9.6%, P<0.001). GRS-C improved classification accuracy for vertebral and non-vertebral fractures by 7.3% (P=0.005) and 3.0% (P=0.091), and GRS-T further improved accuracy by 10.2% (P<0.001) and 4.9% (P=0.008), respectively. Conclusions: Our results suggest that both common and rare functional variants may contribute to OF, and that adding genetic profiling data to current models could improve the prediction of fracture risk in an osteopenic individual.
    The Journal of clinical endocrinology and metabolism. 08/2014;
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by mutations in the dystrophin gene. Adipose-derived stem cells (ASCs)are an attractive source of cells for stem cell therapy. Losartan has been reported to improve ASC transplantation in injured mouse muscles. In the present study, we investigated whether the combinedtreatment of losartan and ASCs in the injured muscles of mdx mice improves regeneration. The combined treatment of ASCs and losartan remarkably improved muscle regeneration and induced muscle hypertrophy. In addition, ASCs and losartan treatment down-regulated transforming growth factor-?(TGF-?) and inhibited muscle fibrosis. We observed cells co-expressing green fluorescent protein (GFP) and dystrophin in the muscle samples of mice transplanted withGFP positive ASCs. In the co-culture in vitroexperiment, we also observed that the GFP-ASCs differentiated into dystrophin expressing myotubes. The present study shows that the combination of transplantedASCs and treatment with losartan ameliorated muscle fibrosis and improved muscle regeneration in injured-mdx mice. Thus, we suggest that combined treatment with losartan and ASCs could help to improve muscle regeneration in the muscles of injured patients, including DMD patients.
    Cell Transplantation 03/2014; · 4.42 Impact Factor
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    ABSTRACT: The time-varying electromagnetic field (EMF) has been widely studied as one of the exogenous stimulation methods for improving bone healing. Our previous study showed that osteogenic differentiation of adipose-derived stem cells was accelerated by a 45-Hz EMF, whereas a 7.5-Hz EMF inhibited osteogenic marker expression. Accordingly, we hypothesized that each negative and positive condition for the osteogenic differentiation could inversely influence osteoclast formation and differentiation. Here, we demonstrated that osteoclast formation, differentiation, and activity can be regulated by altering the frequency of the electromagnetic stimulation, such as 7.5 (negative for osteogenic differentiation) and 45Hz (positive for osteogenic differentiation). A 45Hz EMF inhibited osteoclast formation whereas a 7.5-Hz EMF induced differentiation and activity. Osteoclastogenic markers, such as NFATc1, TRAP, CTSK, MMP9, and DC-STAMP were highly expressed under the 7.5-Hz EMF, while they were decreased at 45Hz. We found that the 7.5-Hz EMF directly regulated osteoclast differentiation through ERK and p38 MAPK activation, whereas the EMF at 45Hz suppressed RANKL-induced phosphorylation of IκB. Additionally, actin ring formation with tubules and bone resorptive activity were enhanced at 7.5Hz through increased integrin β3 expression. However, these were inhibited at 45Hz. Although many questions remain unanswered, our study indicates that osteoclast formation and differentiation were controllable using physical tools, such as an EMF. It will now be of great interest to study the ill-defined correlation between electromagnetic conditions and osteoclast activities, which eventually could lead to determining the therapeutic characteristics of an EMF that will treat bone-related diseases.
    Bone 02/2014; · 4.46 Impact Factor
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    ABSTRACT: Multinucleated osteoclasts differentiate from hematopoietic progenitors of the monocyte/macrophage lineage. Because of its pivotal role in bone resorption, regulation of osteoclast differentiation is a potential therapeutic approach to the treatment of erosive bone disease. In this study, we have found that fucoidan, a sulfated polysaccharide extracted from brown seaweed, inhibited osteoclast differentiation. In particular, addition of fucoidan into the early stage osteoclast cultures significantly inhibited receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced osteoclast formation, thus suggesting that fucoidan affects osteoclast progenitors. Furthermore, fucoidan significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases (MAPKs) such as JNK, ERK, and p38, and also c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. In addition, the activation of NF-κB, which is an upstream transcription factor modulating NFATc1 expression, was alleviated in the fucoidan-treated cells. These results collectively suggest that fucoidan inhibits osteoclastogenesis from bone marrow macrophages by inhibiting RANKL-induced p38, JNK, ERK and NF-κB activation, and by downregulating the expression of genes that partake in both osteoclast differentiation and resorption.
    International Journal of Molecular Sciences 01/2014; 15(10):18840-55. · 2.46 Impact Factor
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    ABSTRACT: Inhibition of an increase of osteoclasts has become the most important treatment for osteoporosis. The CXCR4 antagonist, AMD3100, plays an important role in mobilization of osteoclast precursors within bone marrow (BM). However, the actual therapeutic impact of AMD3100 in osteoporosis has not yet been ascertained. Here we demonstrate the therapeutic effect of AMD3100 in treatment of ovariectomy-induced osteoporosis in mice. We found that treatment with AMD3100 resulted in direct induction of release of SDF-1 from BM to blood and mobilization of hematopoietic stem/progenitor cells (HSPCs) in an osteoporosis model. AMD3100 prevented bone density loss after ovariectomy by mobilization of HSPCs, suggesting a therapeutic strategy to reduce the number of osteoclasts on bone surfaces. These findings support the hypothesis that treatment with AMD3100 can result in efficient mobilization of HSPCs into blood through direct blockade of the SDF-1/CXCR4 interaction in BM and can be considered as a potential new therapeutic intervention for osteoporosis.
    BMB reports 12/2013; · 1.63 Impact Factor
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    ABSTRACT: Osteoclasts are polykaryons that have the unique capacity to degrade bone. Modulation of osteoclast formation and function is a promising strategy for the treatment of bone-destructive diseases. Here, we report that obovatol, a natural compound isolated from Magnolia obovata, inhibits receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation in vitro and inflammatory bone loss in vivo. We found that obovatol strongly inhibited osteoclast formation from bone marrow-derived macrophages in a dose-dependent manner without cytotoxicity. Obovatol significantly suppressed RANKL-induced activation of NF-κB, c-Jun-N-terminal kinase, and extracellular signal-regulated kinase signaling pathways. Obovatol also inhibited RANKL-induced expression of the genes c-Fos and nuclear factor of activated T cells c1, which are transcription factors important for osteoclastogenesis. In addition to osteoclast differentiation, obovatol blocked cytoskeletal organization and abrogated the bone resorbing activity of mature osteoclast. Obovatol also accelerated osteoclast apoptosis through the induction of caspase-3 activation. Consistent with its in vitro anti-resorptive effect, obovatol prevented bone loss induced by lipopolysaccharide in vivo. Together, our data suggest that obovatol may be a useful therapeutic agent for the treatment of pathological bone disorders characterized by excessive osteoclastic bone resorption.
    European journal of pharmacology 10/2013; · 2.59 Impact Factor
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    ABSTRACT: GNF-2, a tyrosine kinase inhibitor, was developed to overcome imatinib-resistant mutations found in CML patients. Osteoclasts are the principal bone-resorbing cells that are responsible for bone diseases, such as osteoporosis, tumor-induced osteolysis, and metastatic cancers. In this study, we investigated the effect of GNF-2 on osteoclast development induced by RANKL and M-CSF. We found that GNF-2 inhibited osteoclast differentiation from BMMs. GNF-2 suppressed RANKL-induced NF-κB transcriptional activity and the induction of c-Fos and NFATc1, which are two key transcription factors in osteoclastogenesis. We also observed that GNF-2 dose-dependently inhibited the proliferation of osteoclast precursors through the suppression of the M-CSFR c-Fms. In addition, GNF-2 accelerated osteoclast apoptosis by inducing caspase-3 and Bim expression. Furthermore, GNF-2 interfered with actin cytoskeletal organization and subsequently blocked the bone-resorbing activity of mature osteoclasts. In agreement with its in vitro effects, GNF-2 reduced osteoclast number and bone loss in a mouse model of LPS-induced bone destruction. Taken together, our data reveal that GNF-2 possesses anti-bone-resorptive properties, suggesting that GNF-2 may have therapeutic value for the treatment of bone-destructive disorders that can occur as a result of excessive osteoclastic bone resorption.
    Journal of leukocyte biology 10/2013; · 4.99 Impact Factor
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    ABSTRACT: PURPOSE: Nitric oxide (NO), a short-lived gaseous free radical, is a potent mediator of biological responses involved in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Nitric oxide also serves as an important signal in physiological processes, including angiogenesis, thrombosis, and bone turnover, which are known to be related to the pathogenesis of osteonecrosis. We investigated whether NOS3 gene polymorphisms are associated with risk of osteonecrosis of the femoral head (ONFH). METHODS: Five polymorphisms in the NOS3 gene were genotyped using TaqMan assays in 306 controls, 150 SLE patients, and 50 SLE patients with ONFH (SLE_ONFH). RESULTS: We found that Asp258Asp and Glu298Asp (G894T) polymorphisms in the NOS3 gene were significantly associated with risk of ONFH. Additionally, we calculated haplotype frequencies of a linkage disequilibrium (LD) block in NOS3 (rs1799983 - rs1800780) and tested for haplotype associations. The haplotypes G-A and T-A showed significant protective (P = 1.6 × 10(-3); OR 0.39, 95 % confidence intervals (CI) 0.22-0.7) and increased risk (P = 2.0 x 10(-5)-6.0 x 10(-4); OR 3.17-3.73) effects for ONFH, respectively. CONCLUSIONS: These results suggest that exonic NOS3 polymorphisms may increase the risk of ONFH in Korean SLE patients.
    International Orthopaedics 06/2013; · 2.32 Impact Factor
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    ABSTRACT: We performed 24 revisions of fractures of third generation ceramic heads. The stem was not changed in 20 revisions; a new ceramic-on-ceramic bearing was used in four and a metal-on-polyethylene bearing in 16. The stem was changed in four revisions; a new ceramic-on-ceramic bearing was used in three and a metal-on-polyethylene bearing in one. During the follow-up of 57.5months, complications occurred in five hips among the 20 stem retained revisions: a fracture of the new ceramic head in two, metallosis with pseudocyst in two, and femoral osteolysis with stem loosening in one. However, there were no complications in the four revisions where the stem was changed. Revision surgery after ceramic head fracture shows high rates of early complications. We recommend stem revision in cases of THA failure due to fracture of a modern ceramic head.
    The Journal of arthroplasty 05/2013; · 1.79 Impact Factor
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    ABSTRACT: LXRs are nuclear receptors that function as important regulators of lipid homeostasis and inflammatory responses. LXR activation has been shown to suppress RANKL-induced osteoclast differentiation, but its underlying mechanisms and its influence on inflammatory bone destruction remain unclear. In this study, we report that the LXR agonists T0901317 and GW3965 inhibit osteoclastogenesis from primary BMMs in a dose-dependent manner. LXR activation suppressed RANKL-induced transcriptional activity of NF-κB without affecting IκBα degradation and the phosphorylation of p38. LXR agonists significantly suppressed RANKL-induced expression of c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. The activation of LXRs also inhibited RANKL-mediated AP-1 transcriptional activity. Furthermore, LXR activation attenuated PPARγ ligand-induced c-Fos expression, and LXR suppressed AP-1 promoter activity by PPARγ. The inhibitory effect of LXR activation on osteoclastogenesis was reversed by overexpression of c-Fos, suggesting that c-Fos is a downstream target of the antiosteoclastogenic action of LXRs. In addition to osteoclast differentiation, LXR activation accelerated apoptosis in mature osteoclasts by the induction of caspase-3 and -9 activity and Bim expression. Consistent with the in vitro effects we observed, the administration of a LXR agonist protected from bone loss induced by LPS in vivo. Together, our data provide evidence that LXRs may have potential as therapeutic targets for bone resorption-associated diseases.
    Journal of leukocyte biology 05/2013; · 4.99 Impact Factor
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    ABSTRACT: Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. This study investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1,229 unrelated Korean postmenopausal women, 39 single-nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis-related traits, such as BMD, osteoporosis, vertebral fracture (VF), non-vertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (model I) GRSs only; (model II) BMD only; (model III) CRFs only; (model IV) CRFs and BMD; and (model V) CRFs, BMD and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis-related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (P = < 0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (P = 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (P = 0.049). In terms of predicting NVF, the area under the receptor-operator characteristics curve (AUC) for model I was 0.55, which was lower than the AUCs of models II (0.60), III (0.64), and IV (0.65). Adding GRS to model IV (in model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (P = 0.014). In terms of predicting any fracture, the AUC of model V (0.68) was similar to that of model IV (0.68), and model V did not significantly improve the accuracy of any fracture classification (P = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2013; · 6.04 Impact Factor
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    ABSTRACT: Ninety-five hips with cementless wedge-shaped tapered CLS stem were evaluated with a mean duration of 12.7years (range, 10.7-17.3years). All patients were young and diagnosed with osteonecrosis of the femoral head. The Harris hip score was 92 at the latest follow-up. A subsidence greater than 3mm was found in 3 hips (3.2%). Focal femoral osteolysis was found in 12 hips (12.6%). Endosteal bone formation and bony pedestal were observed in 94 hips (98.9%) and in 26 hips (27.4%), respectively. With revision for stem loosening as the end point, the survivorship showed 98.9% (95% CI, range 96.9%-100%) at 13years. Stem alignment and proximal femur morphology did not influence loosening of the stem (p>0.05).
    The Journal of arthroplasty 02/2013; · 1.79 Impact Factor
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    ABSTRACT: Carbon monoxide (CO) has been shown to have remarkable therapeutic value at low dosage by suppressing inflammation via inhibitory effects on macrophages, which are also precursors of osteoclasts (OC). The objective of the present study was to determine whether CO limits bone loss through its effects on osteoclastogenesis. Intraperitoneal injection of CO-releasing molecule 2 (CORM2) into mice with reduced bone mass due to ovariectomy (OVX) resulted in significantly elevated bone mass. Increased serum levels of collagen-type I fragments, tartrate-resistant acid phosphatase 5b, and reactive oxygen species (ROS) due to OVX were also decreased when treated with CORM2. In vitro, CORM2 inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced OC formation without affecting bone resorption. CORM2 reduced long-lasting ROS levels and nuclear factor-κB (NF-κB) activation in response to RANKL. Inhibition of NADPH oxidase partially reduced the inhibitory effect of CO. CO induced increase of peroxiredoxin 1 (PRX1) in BMM. Down-regulation of PRX1 reduced the inhibitory effect of CO on OC formation and sustained the ROS levels induced by RANKL, suggesting that CO reduces generation of ROS and scavenges ROS to inhibit osteoclastogenesis. These data suggest that the inhibitory effect of CO on osteoclastogenesis is caused by impaired RANKL signaling through defective NF-κB activation and reduced levels of long-lasting ROS. These changes result in decreased bone loss. Our data highlight the potential utility of CO for ameliorating bone loss induced by loss of ovarian function.
    Biochemical pharmacology 02/2013; · 4.25 Impact Factor
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    ABSTRACT: The developmentally regulated GTP-binding protein 2 (DRG2) is a novel subclass of GTP binding proteins. Many functional characteristics of osteoclast (OC) are associated with small GTPases. We hypothesized that DRG2 affects bone mass via modulating OC activity. Using DRG2 transgenic mice, we investigated the role of DRG2 in bone remodeling. DRG2 overexpression caused a decrease in bone mass and an increase in the number and activity of OC in vivo. DRG2 overexpression increased fusion, spreading, survival, and resorption activity of OC in vitro. Down-regulation of DRG2 by siRNA decreased fusion, spreading, and survival of OC, supporting the observations found in DRG2 transgenic OC. Transgenic mature OCs were larger with actin rings and higher ERK, Akt, Rac1 and Rho activities than wild type OCs. Inhibition of these proteins abolished the effects of DRG2 on formation of large OCs with actin rings, implying that DRG2 affects cytoskeleton reorganization in a Rac1/Rho/ERK/Akt-dependent manner. In summary, DRG2 is associated with survival and cytoskeleton organization of OC under influence of M-CSF, and its overexpression leads to elevated bone resorptive activity of OC, resulting in bone loss.
    AJP Endocrinology and Metabolism 01/2013; · 4.51 Impact Factor
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    ABSTRACT: BACKGROUND: Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. METHODS: Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. RESULTS: In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10(-8); OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. CONCLUSIONS: Our findings provide new insights into the genetic architecture underlying OF in East Asians.
    Journal of Medical Genetics 01/2013; · 5.70 Impact Factor
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    ABSTRACT: AimsOsteoclasts, the unique bone-resorbing polykaryons, are responsible for many bone-destructive diseases, such as osteoporosis and rheumatoid arthritis. Hence, the regulation of osteoclast formation is considered a potential therapeutic approach for these diseases. In this study, we investigated the effect of a novel small compound, C25H32N4O4S2 (NecroX-7) on osteoclast formation.Main methodsWe analyzed the effects of NecoX-7 on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation in vitro and LPS-induced bone loss in vivo.Key findingsWe observed that NecroX-7 suppressed osteoclast formation from primary bone marrow macrophages (BMMs) in a dose-dependent manner. NecroX-7 significantly inhibited the NF-κB signaling pathway without affecting the activation of the mitogen-activated protein kinases (MAPKs) JNK, p38, and ERK in response to RANKL. In addition, NecroX-7 strongly attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are crucial transcription factors for osteoclast differentiation. Mirroring the down-regulation of c-Fos and NFATc1, the expression of osteoclastogenic markers, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was also reduced by the addition of NecroX-7. Furthermore, confirming the in vitro anti-osteoclastogenic effect, NecroX-7 inhibited lipopolysaccharide (LPS)-induced bone loss in vivo.SignificanceOur data imply that NecroX-7 is useful as a therapeutic drug for the treatment of bone resorption-associated diseases.
    Life sciences 11/2012; 91(s 19–20):928–934. · 2.56 Impact Factor
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    ABSTRACT: INTRODUCTION: Despite extensive evidence demonstrating the direct, detrimental role of homocysteine on bone metabolism, the effects of serum total homocysteine (tHcy) on bone loss are still equivocal. In the present study, we performed a longitudinal study on healthy participants of various ages of both sexes in order to investigate the association between serum tHcy concentrations and annualized changes in bone mineral density (BMD). METHODS: A total of 460 Koreans≥30years of age received comprehensive, routine health examinations for an average period of 3years. The BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. RESULTS: After adjusting for potential confounders, the rates of bone loss at the proximal femur sites were significantly accelerated in a dose-response fashion across increasing tHcy concentrations in premenopausal women and men, but not in postmenopausal women. Consistently, compared with subjects in the lowest tHcy quartile, premenopausal women in the third and/or highest tHcy quartile and men in the highest tHcy quartile showed significantly higher rates of bone loss at all proximal femur sites (p=0.015-0.048) and at the total femur and femur neck (p=0.008-0.013), respectively. In contrast, there were no differences in terms of bone loss among the tHcy quartiles for postmenopausal women. CONCLUSION: These data provide the first clinical evidence that increased tHcy levels could be an independent risk factor for the future deterioration of bone mass in premenopausal women and men.
    Bone 09/2012; 52(1):56-62. · 4.46 Impact Factor

Publication Stats

1k Citations
380.81 Total Impact Points

Institutions

  • 2005–2014
    • Kyungpook National University Hospital
      Sŏul, Seoul, South Korea
    • Kyungpook National University
      • • Department of Orthopaedic Surgery
      • • School of Dentistry
      Daikyū, Daegu, South Korea
  • 2010–2013
    • University of Ulsan
      • Department of Biological Sciences
      Urusan, Ulsan, South Korea
    • Andong National University
      • Department of Mechanical Engineering
      Andong, North Gyeongsang, South Korea
    • Jeju National University
      Tse-tsiu, Jeju, South Korea
  • 2012
    • Wonkwang University School of Medicine and Hospital
      Riri, North Jeolla, South Korea
  • 2010–2012
    • Ulsan University Hospital
      Urusan, Ulsan, South Korea
  • 2011
    • Seoul National University Bundang Hospital
      • Department of Orthopaedic Surgery
      Sŏul, Seoul, South Korea
  • 2010–2011
    • Chung-Ang University Hospital
      Sŏul, Seoul, South Korea
  • 2009
    • Pohang University of Science and Technology
      • Department of Mechanical Engineering
      Andong, North Gyeongsang, South Korea
  • 2008
    • Seoul National University Hospital
      • Department of Orthopedic Surgery
      Seoul, Seoul, South Korea
    • Keimyung University
      • Dongsan Medical Center
      Seoul, Seoul, South Korea
  • 2007
    • Gyeongsang National University
      • Department of Orthopaedic Surgery
      Chinju, South Gyeongsang, South Korea
  • 2004–2006
    • Asan Medical Center
      • Department of Endocrinology/Metabolism
      Seoul, Seoul, South Korea