The inhibitory effect of beta-lapachone on RANKL-induced osteoclastogenesis

Gu, Dong Ryun,Lee, Joon No,Oh, Gi-Su,Kim, Hyung Jin,Kim, Min Seuk,Lee, Seoung Hoon Elsevier 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. β-L inhibited osteoclast formation in a dose-dependent manner and also reduced the expression of osteoclast differentiation marker genes, such as tartrate-resistant acid phosphatase (<I>Acp5</I> or <I>TRAP</I>), cathepsin K (<I>CtsK</I>), the d2 isoform of vacuolar ATPase V0 domain (<I>Atp6v0d2</I>), osteoclast-associated receptor (<I>Oscar</I>), and dendritic cell-specific transmembrane protein (<I>Dc-stamp</I>). β-L treatment of RANKL-induced osteoclastogenesis significantly increased the cellular NAD+/NADH ratio and resulted in the activation of 5′ AMP-activated protein kinase (AMPK), a negative regulator of osteoclast differentiation. In addition, β-L treatment led to significant suppression of the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β), which can stimulate osteoclastogenesis. β-L treatment downregulated c-Fos and nuclear factor of activated T-cells 1 (NFATc1), which are master transcription factors for osteoclastogenesis. Taken together, the results demonstrated that β-L inhibits RANKL-induced osteoclastogenesis and could be considered a potent inhibitor of RANKL-mediated bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> β-lapachone (β-L) inhibits RANKL-mediated osteoclastogenesis. </LI> <LI> β-L increases the intracellular NAD+/NADH ratio, which is followed by activation of AMPK in osteoclasts. </LI> <LI> The activation of AMPK by β-L inhibits c-Fos and NFATc1 expression in RANKL-induced osteoclastogenesis. </LI> <LI> β-L also suppresses c-Fos and NFATc1 expression via downregulation of PPARγ and PGC1β expression. </LI> </UL> </P>

Inhibitory Effect of <i>Chrysanthemum zawadskii</i> Herbich var. <i>latilobum</i> Kitamura Extract on RANKL-Induced Osteoclast Differentiation

Gu, Dong Ryun,Hwang, Jin-Ki,Erkhembaatar, Munkhsoyol,Kwon, Kang-Beom,Kim, Min Seuk,Lee, Young-Rae,Lee, Seoung Hoon Hindawi Publishing Corporation 2013 Evidence-based Complementary and Alternative Medic Vol.2013 No.-

<P><I>Chrysanthemum zawadskii Herbich</I> var. <I>latilobum Kitamura</I>, known as “Gujulcho” in Korea, has been used in traditional medicine to treat various inflammatory diseases, including rheumatoid arthritis. However, these effects have not been tested on osteoclasts, the bone resorbing cells that regulate bone metabolism. Here, we investigated the effects of <I>C. zawadskii</I> Herbich var. <I>latilobum</I> Kitamura ethanol extract (CZE) on osteoclast differentiation induced by treatment with the receptor activator of NF-<I><I>κ</I></I>B ligand (RANKL). CZE inhibited osteoclast differentiation and formation in a dose-dependent manner. The inhibitory effect of CZE on osteoclastogenesis was due to the suppression of ERK activation and the ablation of RANKL-stimulated Ca<SUP>2+</SUP>-oscillation via the inactivation of PLC<I><I>γ</I></I>2, followed by the inhibition of CREB activation. These inhibitory effects of CZE resulted in a significant repression of c-Fos expression and a subsequent reduction of NFATc1, a key transcription factor for osteoclast differentiation, fusion, and activation <I>in vitro</I> and <I>in vivo</I>. These results indicate that CZE negatively regulates osteoclast differentiation and may be a therapeutic candidate for the treatment of various bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis.</P>

2차원 유한요소법을 적용한 플라이휠 에너지 저장 장치 동특성 해석 프로그램 개발

구동식(Dong Sik Gu),배용채(Yong Cae Bae),이욱륜(Wook Ryun Lee),김재구(Jae Gu Kim),김효중(Hyo Jung Kim),최병근(Byeong Keun Choi) 대한기계학회 2010 大韓機械學會論文集A Vol.34 No.11

플라이휠 에너지 저장 장치는 잉여 전기를 회전관성을 통해 운동 에너지로 저장하는 장치로, 회전의 중심이 되는 축과 외부의 플라이휠로 구성이 된다. 수치해석을 위한 일반적 프로그램들은 3차원의 모델을 통하여 구조해석 및 주파수 응답 등의 해석을 수행하게 된다. 허나 상용 프로그램을 이용한 동역학적 해석의 응용은 매우 어려운 실정이며, 사용자가 그 방법을 익히는 것 또한 쉽지 않다. 이러한 문제들을 보완하고자 동역학적 해석을 위한 프로그램을 2차원의 모델을 사용하여 구축하였다. 본 논문에서 제시한 모델링은 회전체를 2차원으로 표현함으로써 3차원에 비해 시스템의 표현을 보다 단순화하여 시스템의 구조를 쉽게 이해할 수 있도록 하였으며, 회전체를 서로 다른 재질의 다중 레이어로 모델이 가능하게 하였다. 또한 축계에 추가적 강성의 영향을 줄 수 있는 열박음 부분에 대하여, 그 영향 정도를 선택적으로 입력할 수 있게 하여 열박음에 대한 효과를 조정할 수 있도록 하였다. 따라서 본 논문에서 제시하는 2차원 모델을 이용한 동특성 해석 프로그램의 해석 오차를 알아보기 위해 상용 프로그램의 해석 결과와 비교하였으며, 모델링을 위한 시간과 해석 수행 시간 역시 비교하였다. Flywheel energy storage system (FESS) is defined as a high speed rotating flywheel system that can save surplus electric power. The FESS is proposed as an efficient energy storage system because it can accumulate a large amount of energy when it is operated at a high rotating speed and no mechanical problems are encountered. The FESS consists of a shaft, flywheel, motor/generator, bearings, and case. It is difficult to simulate rotor dynamics using common structure simulation programs because these programs are based on the 3D model and complex input rotating conditions. Therefore, in this paper, a program for the FESS based on the 2D FEM was developed. The 2D FEM can model easier than 3D, and it can present the multi-layer rotor with different material each other. Stiffness changing of the shaft caused by shrink fitting of the hub can be inputted to get clear solving results. The results obtained using the program were compared with those obtained using the common programs to determine any errors.

플라이휠 에너지 저장 장치의 회전 동특성 해석을 위한 2D 모델링 방법 제시

구동식(Dong Sik Gu),배용채(Yong Chae Bae),이욱륜(Wook Ryun Lee),최병근(Byeong Keun Choi) 한국소음진동공학회 2010 한국소음진동공학회 학술대회논문집 Vol.2010 No.4

Lysosomal Ca²⁺Signaling is Essential for Osteoclastogenesis and Bone Remodeling : LYSOSOMAL CA²⁺SIGNALING ESSENTIAL FOR OSTEOCLASTOGENESIS & BONE REMODELING

Erkhembaatar, Munkhsoyol,Gu, Dong Ryun,Lee, Seoung Hoon,Yang, Yu-Mi,Park, Soonhong,Muallem, Shmuel,Shin, Dong Min,Kim, Min Seuk Wiley-Blackwell Publishing, Inc. 2017 Journal of Bone and Mineral Research Vol. No.

<P>Lysosomal Ca2+ emerges as a critical component of receptor-evoked Ca2+ signaling and plays a crucial role in many lysosomal and physiological functions. Lysosomal Ca2+ release is mediated by the transient receptor potential (TRP) family member TRPML1, mutations that cause the lysosomal storage disease mucolipidosis type 4. Lysosomes play a key role in osteoclast function. However, nothing is known about the role of lysosomal Ca2+ signaling in osteoclastogenesis and bone metabolism. In this study, we addressed this knowledge gap by studying the role of lysosomal Ca2+ signaling in osteoclastogenesis, osteoclast and osteoblast functions, and bone homeostasis in vivo. We manipulated lysosomal Ca2+ signaling by acute knockdown of TRPML1, deletion of TRPML1 in mice, pharmacological inhibition of lysosomal Ca2+ influx, and depletion of lysosomal Ca2+ storage using the TRPML agonist ML-SA1. We found that knockdown and deletion of TRPML1, although it did not have an apparent effect on osteoblast differentiation and bone formation, markedly attenuated osteoclast function, RANKL-induced cytosolic Ca2+ oscillations, inhibited activation of NFATc1 and osteoclastogenesis-controlling genes, suppressed the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs), and markedly reduced the differentiation of bone marrow-derived macrophages into osteoclasts. Moreover, deletion of TRPML1 resulted in enlarged lysosomes, inhibition of lysosomal secretion, and attenuated the resorptive activity of mature osteoclasts. Notably, depletion of lysosomal Ca2+ with ML-SA1 similarly abrogated RANKL-induced Ca2+ oscillations and MNC formation. Deletion of TRPML1 in mice reduced the TRAP-positive bone surfaces and impaired bone remodeling, resulting in prominent osteopetrosis. These findings demonstrate the essential role of lysosomal Ca2+ signaling in osteoclast differentiation and mature osteoclast function, which play key roles in bone homeostasis. (C) 2016 American Society for Bone and Mineral Research.</P>

Inhibitory effect of Chaenomelis Fructus ethanol extract on receptor activator of nuclear factor-kappa B ligand-mediated osteoclastogenesis

Geun Ha Park,Dong Ryun Gu,and Seoung Hoon Lee 대한구강생물학회 2020 International Journal of Oral Biology Vol.45 No.1

The fruit of Chaenomeles sinensis (Thouin) Koehne (Chaenomelis Fructus) known as “Mo-Gua” in Korea has been commonly used in traditional medicine to treat inflammatory diseases, such as sore throat. However, its effect on bone metabolism has not been elucidated yet. Here, we examined the effect of Chaenomelis Fructus ethanol extract (CFE) on receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated osteoclast differentiation and formation. CF-E considerably inhibited osteoclast differentiation and tartrate-resistant acid phosphatase-positive multinuclear cell formation from bone marrow-derived macrophages and osteoclast precursor cells in a dose-dependent manner. In addition, the formation of actin rings and resorption pits were significantly suppressed in CF-E-treated osteoclasts as compared with the findings in non-treated control cells. Consistent with these phenotypic inhibitory results, the expressions of osteoclast differentiation marker genes (Acp5, Atp6v0d2 , Oscar, CtsK, and Tm7sf4) and Nfatc1 , a pivotal transcription factor for osteoclastogenesis, were markedly decreased by CF-E treatment. The inhibitory effect of CF-E on RANKL-induced osteoclastogenesis was associated with the suppression of NFATc1 expression, not by regulation of mitogen-activated protein kinases and NF-κB activation but by the inactivation of phospholipase C gamma 1 and 2. These results indicate that CF-E has an inhibitory effect on osteoclast differentiation and formation, and they suggest the possibility of CF-E as a traditional therapeutic agent against bone-resorptive diseases, such as osteoporosis, rheumatoid arthritis, and periodontitis.

우리나라 응급진료권 규명에 관한 연구<상>

장동민,김용억,이석구,문옥륜,Jang, Dong-Min,Kim, Yong-Eok,Lee, Seok-Gu,Mun, Ok-Ryun 대한병원협회 1990 대한병원협회지 Vol.19 No.10

Actin-binding LIM protein 1 regulates receptor activator of NF-kB ligand-mediated osteoclast differentiation and motility

( Su Hyun Jin ),( Hyunsoo Kim ),( Dong Ryun Gu ),( Keun Ha Park ),( Young Rae Lee ),( Yongwon Choi ),( Seoung Hoon Lee ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.7

Actin-binding LIM protein 1 (ABLIM1), a member of the LIM-domain protein family, mediates interactions between actin filaments and cytoplasmic targets. However, the role of ABLIM1 in osteoclast and bone metabolism has not been reported. In the present study, we investigated the role of ABLIM1 in the receptor activator of NF-kB ligand (RANKL)- mediated osteoclastogenesis. ABLIM1 expression was induced by RANKL treatment and knockdown of ABLIM1 by retrovirus infection containing Ablim1-specific short hairpin RNA (shAblim1) decreased mature osteoclast formation and bone resorption activity in a RANKL-dose dependent manner. Coincident with the downregulated expression of osteoclast differentiation marker genes, the expression levels of c-Fos and the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), critical transcription factors of osteoclastogenesis, were also decreased in shAblim1-infected osteoclasts during RANKLmediated osteoclast differentiation. In addition, the motility of preosteoclast was reduced by ABLIM1 knockdown via modulation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt/Rac1 signaling pathway, suggesting another regulatory mechanism of ABLIM1 in osteoclast formation. These data demonstrated that ABLIM1 is a positive regulator of RANKLmediated osteoclast formation via the modulation of the differentiation and PI3K/Akt/Rac1-dependent motility. [BMB Reports 2018; 51(7): 356-361]

플라이휠 에너지 저장 장치의 2D모델링 방법 제시

김병수(Byeong-Su Kim),구동식(Dong-Sik Gu),임장익(Jang-Ik Lim),배용채(Yong-Chae Bae),이욱륜(Wook-Ryun Lee),김희수(Hee-Su Kim),최병근(Byeong-Keun Choi) 대한기계학회 2009 대한기계학회 춘추학술대회 Vol.2009 No.11

The purpose of flywheel energy storage system (FESS) is to store unused nighttime electricity as kinetic energy and convert it to electricity during daytime. The FESS is proposed as an effcient energy storage system because there is no mechanical problems, such as friction and wear. The flywheel is rotated at a high speed, 10,000 rpm. The rotor dynamic analysis should be performed with a adequate analytical model and equations of motion to identify the stable driving condition and the dynamic behavior. But the analysis has to be needed for a long time to get the result from solving software that is used 3D model because the number of node and element is very big for good result. Therefore, in this paper, the new modelling method using 2D model is suggested. It will be solved by coded program in MATLAB by FEM(Finite Element Method). And the result from coded program is compared with results from common solving software, MSC. Nastran and ANSYS Workbench.

우리나라 응급진료권 규명에 관한 연구 <하>

장동민,김용억,이석구,문옥륜,Jang, Dong-Min,Kim, Yong-Eok,Lee, Seok-Gu,Mun, Ok-Ryun 대한병원협회 1990 대한병원협회지 Vol.19 No.11