Anticancer Effect of Korean Red Ginseng Extract in Acute Promyelocytic Leukemia

Sungsin Jo,Hongki Lee,Sojin Kim,Heekyoung Chung(정희경) 고려인삼학회 2010 고려인삼학회 학술대회 Vol.2010 No.12

IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis

Jo, Sungsin,Wang, Sung Eun,Lee, Young Lim,Kang, Suman,Lee, Bitnara,Han, Jinil,Sung, Il-Hoon,Park, Ye-Soo,Bae, Sang-Cheol,Kim, Tae-Hwan BioMed Central 2018 Arthritis research & therapy Vol.20 No.-

<P><B>Background</B></P><P>IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.</P><P><B>Methods</B></P><P>TNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.</P><P><B>Results</B></P><P>Basal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.</P><P><B>Conclusions</B></P><P>Our findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (10.1186/s13075-018-1582-3) contains supplementary material, which is available to authorized users.</P>

Identification and characterization of human bone-derived cells

Jo, Sungsin,Lee, Jin Kyu,Han, Jinil,Lee, Bitnara,Kang, Suman,Hwang, Kyu-Tae,Park, Ye-Soo,Kim, Tae-Hwan Elsevier 2018 Biochemical and biophysical research communication Vol.495 No.1

<P><B>Abstract</B></P> <P>This study was designed to identify and characterize primary bone-derived cells (BdCs) and investigate the potential role of osteoblast differentiation. Primary BdCs were isolated from surgical bone for comparative analysis with mesenchymal stem cells (MSCs) and fetal osteoblasts (FOBs) and for potential differentiation to mature osteoblasts. Using three different cells, we successfully cultivated human osteoblast differentiation and activity which were evaluated using microarray and biochemical methods. BdCs are more correlated to MSCs in bioinformatics result and similar with FOBs in gene expression. In particular, Osterix, osteoprogenitor marker, was high expressed in BdCs, while the expression in MSCs and FOBs were very low. Furthermore, BdCs exhibited a marked alkaline phosphatase (ALP) expression, early stage of osteogenic marker, and retained osteogenic properties and physiological changes into maturation as in FOBs. BdCs also showed an increase in bone morphogenic protein 2 (BMP2), osteopontin (OPN), and osteocalcin (OCN) mRNA expressions during differentiation. This study suggests that BdCs may be osteoprogenitor cells or undifferentiated preosteoblasts with strong capacity to differentiate toward mature osteoblasts.</P> <P><B>Highlights</B></P> <P> <UL> <LI> In non-osteogenic condition, BdCs are more correlated to MSCs than FOBs in bioinformatics result. </LI> <LI> BdCs sustained not only high ALP, OPN and osterix expression, but differentiated to mature osteoblast. </LI> <LI> In osteogenic condition, BdCs are similar with FOBs than MSCs in physiological changes results. </LI> <LI> We suggest BdCs are osteoprogenitor cells or undifferentiated preosteoblasts. </LI> </UL> </P>

CCAAT/enhancer-binding protein beta (C/EBPβ) is an important mediator of 1,25 dihydroxyvitamin D3 (1,25D3)-induced receptor activator of nuclear factor kappa-B ligand (RANKL) expression in osteoblasts

( Sungsin Jo ),( Yun Young Lee ),( Jinil Han ),( Young Lim Lee ),( Subin Yoon ),( Jaehyun Lee ),( Younseo Oh ),( Joong-soo Han ),( Il-hoon Sung ),( Ye-soo Park ),( Tae-hwan Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.6

Receptor activator of nuclear factor kappa B ligand (RANKL) expression in osteoblasts is regulated by 1,25-dihydroxyvitamin D3 (1,25D3). CCAAT/enhancer-binding protein beta (C/EBPβ) has been proposed to function as a transcription factor and upregulate RANKL expression, but it is still uncertain how C/EBPβ is involved in 1,25D3-induced RANKL expression of osteoblasts. 1,25D3 stimulation increased the expression of RANKL and C/EPBβ genes in osteoblasts and enhanced phosphorylation and stability of these proteins. Moreover, induction of RANKL expression by 1,25D3 in osteoblasts was downregulated upon knockdown of C/EBPβ. In contrast, C/EBPβ overexpression directly upregulated RANKL promoter activity and exhibited a synergistic effect on 1,25D3-induced RANKL expression. In particular, 1,25D3 treatment of osteoblasts increased C/EBPβ protein binding to the RANKL promoter. In conclusion, C/EBPβ is required for induction of RANKL by 1,25D3. [BMB Reports 2019; 52(6): 391-396]

A novel role for bone-derived cells in ankylosing spondylitis: Focus on IL-23

Jo, Sungsin,Koo, Bon San,Lee, Bitnara,Kwon, Eunji,Lee, Young Lim,Chung, Heekyoung,Sung, Il-Hoon,Park, Ye-Soo,Kim, Tae-Hwan Elsevier 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPβ to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPβ genes, leading to IL-23 production.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Bones and its-derived cells from patients with AS showed an increase in ER stress. </LI> <LI> IL-23 cytokine was significantly higher in AS patients than in healthy controls. </LI> <LI> Inducing ER stress in AS exhibited an increase of bone-related genes. </LI> <LI> Inducing ER stress in AS was accompanied with augmentation of IL-23 cytokine. </LI> <LI> ER stress-induced RUNX2 is involved in IL-23 secretion and bone-related genes. </LI> </UL> </P>

Accelerated osteogenic differentiation of human bone-derived cells in ankylosing spondylitis

Jo, Sungsin,Kang, Suman,Han, Jinil,Choi, Seung Hyun,Park, Ye-Soo,Sung, Il-Hoon,Kim, Tae-Hwan Springer-Verlag 2018 Journal of bone and mineral metabolism Vol.36 No.3

The TNF-NF-κB-DKK1 Axis Promoted Bone Formation in the Enthesis of Ankylosing Spondylitis

( Sungsin Jo ),( Bora Nam ),( Young Lim Lee ),( Hyosun Park ),( Subin Weon ),( Sung-hoon Choi ),( Ye-soo Park ),( Tae-hwan Kim ) 대한류마티스학회 2021 대한류마티스학회지 Vol.28 No.4

Objective. This study aimed to determine the serum Dickkopf 1 (DKK1) levels in ankylosing spondylitis (AS) patients and decipher the mechanism of tumor necrosis factor (TNF)-mediated DKK1 regulation in human AS enthesis cells. Methods. The sera were obtained from 103 patients with AS and 30 healthy controls (HCs). The enthesis of facet joints were obtained from 4 AS patients and 5 controls. The serum levels of DKK1 were measured using ELISA and compared between AS and HCs. The impact of TNF on DKK1 expression in human primary spinal enthesis cells was evaluated using various molecular biology techniques and bone formation indicators. Results. AS patients showed higher serum DKK1 levels than HCs after adjusting for age (917.4 [615.3∼1,310.0] pg/mL vs. 826.2 [670.3∼927.8] pg/mL, p=0.043). TNF treatment promoted bone formation and DKK1 expression in both control enthesis cells and those of AS. This enhanced bone formation by TNF was pronounced in AS-enthesis than those of controls. Mechanically, TNF induced NF-κB activation upregulates the DKK1 transcript level. While, NF-κB inhibitor led to downregulate DKK1 expression in the enthesis. Besides, DKK1 overexpression promoted bone formation in enthesis. Conclusion. TNF induced DKK1 expression in the enthesis through NF-κB activation. TNF-induced DKK1 expression may play a bone formation in the radiologic progression of ankylosing spondylitis. (J Rheum Dis 2021;28:216-224)

Dikkopf-1 promotes matrix mineralization of osteoblasts by regulating Ca+-CAMK2A- CREB1 pathway

박효선,Sungsin Jo,Mi-Ae Jang,Sung Hoon Choi,Tae-Hwan Kim 생화학분자생물학회 2022 BMB Reports Vol.55 No.12

Dickkopf-1 (DKK1) is a secreted protein that acts as an antagonistof the canonical WNT/β-catenin pathway, which regulatesosteoblast differentiation. However, the role of DKK1 on osteoblastdifferentiation has not yet been fully clarified. Here, weinvestigate the functional role of DKK1 on osteoblast differentiation. Primary osteoprogenitor cells were isolated from humanspinal bone tissues. To examine the role of DKK1 in osteoblastdifferentiation, we manipulated the expression of DKK1, andthe cells were differentiated into mature osteoblasts. DKK1 overexpressionin osteoprogenitor cells promoted matrix mineralizationof osteoblast differentiation but did not promote matrixmaturation. DKK1 increased Ca+ influx and activation of theCa+/calmodulin-dependent protein kinase II Alpha (CAMK2A)-cAMP response element-binding protein 1 (CREB1) and increasedtranslocation of p-CREB1 into the nucleus. In contrast, stable DKK1knockdown in human osteosarcoma cell line SaOS2 exhibitedreduced nuclear translocation of p-CREB1 and matrix mineralization. Overall, we suggest that manipulating DKK1 regulatesthe matrix mineralization of osteoblasts by Ca+-CAMK2A-CREB1,and DKK1 is a crucial gene for bone mineralization of osteoblasts.

SUZ12 inhibition attenuates cell proliferation of glioblastoma via post-translational regulation of CDKN1B

Kim Sojin,Jo Sungsin,Paek Sun Ha,Kang Sang Soo,Chung Heekyoung 한국유전학회 2023 Genes & Genomics Vol.45 No.12

Background Human gliomas are aggressive brain tumors characterized by uncontrolled cell proliferation. Differential expression of Polycomb repressive complex 2 (PRC2) has been reported in various subtypes of glioma. However, the role of PRC2 in uncontrolled growth in glioma and its underlying molecular mechanisms remain to be elucidated. Objective We aimed to investigate the functional role of PRC2 in human glioblastoma cell growth by silencing SUZ12, the non-catalytic core component of PRC2. Methods Knockdown of SUZ12 was achieved by infecting T98G cells with lentivirus carrying sequences specifically targeting SUZ12 (shSUZ12). Gene expression was examined by quantitative PCR and western analysis. The impact of shSUZ12 on cell growth was assessed using a cell proliferation assay. Cell cycle distribution was analyzed by flow cytometry, and protein stability was evaluated in cycloheximide-treated cells. Subcellular localization was examined through immunofluorescence staining and biochemical cytoplasmic-nuclear fractionation. Gene expression analysis was also performed on human specimens from normal brain and glioblastoma patients. Results SUZ12 knockdown (SUZ12 KD) led to widespread decrease in the PRC2-specific histone mark, accompanied by a slowdown of cell proliferation through G1 arrest. In SUZ12 KD cells, the degradation of CDKN1B protein was reduced, resulting from alterations in the MYC-SKP2-CDKN1B axis. Furthermore, nuclear localization of CDKN1B was enhanced in SUZ12 KD cells. Analysis of human glioblastoma samples yielded increased expression of EZH2 and MYC along with reduced CDKN1B compared to normal human brain tissue. Conclusion Our findings suggest a novel role for SUZ12 in cell proliferation through post-translational regulation of CDKN1B in glioblastoma.

Poly-γ-glutamic acid suppresses osteoclastogenesis in human osteoclast precursors and prevents joint damage in a collagen-induced murine arthritis model

Lee, Bitnara,Jo, Sungsin,Kim, Sung-Min,Cho, Mi-La,Park, Sung-Hwan,Youn, Jeehee,Ji, Jong Dae,Kim, Tae-Hwan Elsevier 2018 IMMUNOLOGY LETTERS Vol.203 No.-

<P><B>Abstract</B></P> <P>Poly–γ-glutamic acid (γ-PGA), a natural polymer derived from <I>Bacillus subtilis</I>, shows anti-inflammatory activity. However, the effects of γ-PGA on osteoclasts, which are important cells for joint destruction in inflammatory diseases such as rheumatoid arthritis (RA), have not yet been reported. In this study, we show that γ-PGA markedly inhibits osteoclast differentiation in normal PBMC-derived osteoclast precursors and in synovial fluid macrophages of patients with RA. γ-PGA also reduces RANK expression by down-regulating M-CSF receptors. Additionally, oral administration of γ-PGA attenuated bone destruction in a collagen-induced arthritis (CIA) model, demonstrating decreases in inflammation, cartilage damage, and osteoclast formation in histological analyses. Taken together, these data suggest that γ-PGA could be a good candidate for therapeutic prevention of joint destruction in RA.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Poly-γ-glutamic acid (γ-PGA) inhibited osteoclast differentiation in normal PBMC-derived osteoclast precursors and RA synovial fluid macrophages. </LI> <LI> Treatment with γ-PGA suppressed osteoclastogenesis <I>in vitro</I> and <I>in vivo</I>. </LI> <LI> Oral administration of γ-PGA markedly reduced bone destruction in collagen-induced mouse (CIA) model. </LI> </UL> </P>