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>

Complex object wave extraction using time-multiplexing in off-axis digital holography

Dashdavaa, Erkhembaatar,Erdenebat, Munkh-Uchral,Shin, Chang-Won,Kim, Nam OSA OPTICAL SOCIETY OF AMERICA 2018 Applied optics Vol.57 No.1

<P>In this paper, we present an algorithm for complex object wave extraction in off-axis digital holography using a time-multiplexing and frequency spectrum-shifting technique. The proposed approach utilizes the digital time-multiplexing technique, in which two 90-deg-rotated off-axis holograms are recorded in sequence, and corresponding spectra are subtracted in the computed Fourier domain to eliminate the DC term. Then, the two subtracted holograms are digitally multiplexed into one complex hologram in the same plane, and by shifting the spatial frequency spectra of the subtracted hologram in the spatial frequency domain, one of the two cross-correlations can be obtained in the center. This technique simply extracts the spectrum of the real image in the frequency domain than the spatial filtering method. (C) 2017 Optical Society of America</P>

Study on distribution of information potential

Narantuya Erkhembaatar 한국정보통신학회 2007 2016 INTERNATIONAL CONFERENCE Vol.1 No.1

Constituents Released from Streptococcus mutans Attenuate Arecolinemediated Cytotoxicity in HGF Cells by Altering Intracellular Ca2+ Signaling

Munkhsoyol Erkhembaatar,Hyuncheol Oh,Min Seuk Kim KOREAN ACADAMY OF ORAL BIOLOGY 2014 International Journal of Oral Biology Vol.39 No.1

Streptococcus mutans (S. mutans) is a facultative anaerobic bacterium mainly found in the oral cavity and is known to contribute to tooth decay and gingivitis. Recent studies on intestinal microbiota have revealed that microorganisms forming a biofilm play important roles in maintaining tissue homeostasis through their own metabolism. However, the physiological roles of oral microorganisms such as S. mutans are still unclear. In our current study, we identified that constituents released from S. mutans (CR) reduce arecolinemediated cytotoxicity without producing toxic effects themselves. Arecoline, as a major alkaloid of areca nut, is known to mediate cytotoxicity on oral epithelial cells and induces a sustained intracellular Ca2+ ([Ca2+]i) increase that is cytotoxic. The exposure of human gingival fibroblast (HGF) cells to CR not only inhibited the sustained [Ca2+]i increase but also the initial [Ca2+]i elevation. In contrast, CR had no effects on the gene regulation mediated by arecoline. These results demonstrate that S. mutans has physiological role in reducing cytotoxicity in HGF cells and may be considered a novel pharmaceutical candidate.

<i>Glechoma hederacea</i> Suppresses RANKL-mediated Osteoclastogenesis

Hwang, J.K.,Erkhembaatar, M.,Gu, D.R.,Lee, S.H.,Lee, C.H.,Shin, D.M.,Lee, Y.R.,Kim, M.S. Journal of Dental Research, Inc 2014 Journal of dental research Vol.93 No.7

<P> <I>Glechoma hederacea</I> (GH), commonly known as ground-ivy or gill-over-the-ground, has been extensively used in folk remedies for relieving symptoms of inflammatory disorders. However, the molecular mechanisms underlying the therapeutic action of GH are poorly understood. Here, we demonstrate that GH constituents inhibit osteoclastogenesis by abrogating receptor activator of nuclear κ-B ligand (RANKL)-induced free cytosolic Ca<SUP>2+</SUP> ([Ca<SUP>2+</SUP>]<SUB>i</SUB>) oscillations. To evaluate the effect of GH on osteoclastogenesis, we assessed the formation of multi-nucleated cells (MNCs), enzymatic activity of tartrate-resistant acidic phosphatase (TRAP), expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), and [Ca<SUP>2+</SUP>]<SUB>i</SUB> alterations in response to treatment with GH ethanol extract (GHE) in primarily cultured bone marrow–derived macrophages (BMMs). Treatment of RANKL-stimulated or non-stimulated BMMs with GHE markedly suppressed MNC formation, TRAP activity, and NFATc1 expression in a dose-dependent manner. Additionally, GHE treatment induced a large transient elevation in [Ca<SUP>2+</SUP>]<SUB>i</SUB> while suppressing RANKL-induced [Ca<SUP>2+</SUP>]<SUB>i</SUB> oscillations, which are essential for NFATc1 activation. GHE-evoked increase in [Ca<SUP>2+</SUP>]<SUB>i</SUB> was dependent on extracellular Ca<SUP>2+</SUP> and was inhibited by 1,4-dihydropyridine (DHP), inhibitor of voltage-gated Ca<SUP>2+</SUP> channels (VGCCs), but was independent of store-operated Ca<SUP>2+</SUP> channels. Notably, after transient [Ca<SUP>2+</SUP>] elevation, treatment with GHE desensitized the VGCCs, resulting in an abrogation of RANKL-induced [Ca<SUP>2+</SUP>]<SUB>i</SUB> oscillations and MNC formation. These findings demonstrate that treatment of BMMs with GHE suppresses RANKL-mediated osteoclastogenesis by activating and then desensitizing DHP-sensitive VGCCs, suggesting potential applications of GH in the treatment of bone disorders, such as periodontitis, osteoporosis, and rheumatoid arthritis.</P>

Advanced 360-Degree Integral-Floating Display Using a Hidden Point Removal Operator and a Hexagonal Lens Array

Munkh-Uchral Erdenebat,권기철,Erkhembaatar Dashdavaa,Yan-Ling Piao,유관희,Ganbat Baasantseren,김영민,김남 한국광학회 2014 Current Optics and Photonics Vol.18 No.6

An enhanced 360-degree integral-floating three-dimensional display system using a hexagonal lens array and a hidden point removal operator is proposed. Only the visible points of the chosen three-dimensional point cloud model are detected by the hidden point removal operator for each rotating step of the anamorphic optics system, and elemental image arrays are generated for the detected visible points from the corresponding viewpoint. Each elemental image of the elemental image array is generated by a hexagonal grid, due to being captured through a hexagonal lens array. The hidden point removal operator eliminates the overlap problem of points in front and behind, and the hexagonal lens array captures the elemental image arrays with more accurate approximation, so in the end the quality of the displayed image is improved. In an experiment, an anamorphic-optics-system-based 360-degree integral-floating display with improved image quality is demonstrated.

Peucedanum japonicum Thunb. ethanol extract suppresses RANKL-mediated osteoclastogenesis

Kim, Jeong-Mi,Erkhembaatar, Munkhsoyol,Lee, Guem-San,Lee, Jin-Hyun,Noh, Eun-Mi,Lee, Minok,Song, Hyun-Kyung,Lee, Choong Hun,Kwon, Kang-Beom,Kim, Min Seuk,Lee, Young-Rae Spandidos Publications 2017 Experimental and therapeutic medicine Vol.14 No.1

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>

UV Photocatalysis of Bone Marrow-Derived Macrophages on TiO₂Nanotubes Mediates Intracellular Ca²⁺Influx via Voltage-Gated Ca²⁺Channels

Oh, Seunghan,Choi, Eun-Joo,Erkhembaatar, Munkhsoyol,Kim, Min Seuk Hindawi Limited 2015 Journal of nanomaterials Vol.2015 No.-

<P>Titanium (Ti) possesses excellent properties for use in dental implants but has low osteogenic surface properties that result in limiting rapid osseointegration. The physiological interaction between the surface of the implant material and bone cells, especially osteoclasts, is a crucial factor in determining successful osseointegration. However, the details of such an interaction remain elusive. Here, we demonstrated that nanotopography on the Ti surface is a crucial factor for modulating intracellular signal transduction in bone marrow-derived macrophages (BMMs). To define this, intracellular Ca<SUP>2+</SUP>and ROS were simultaneously measured in BMMs that were seeded on polished Ti and TiO2nanotubes. We found that UV photocatalysis of TiO2immediately elicits intracellular calcium concentration ([Ca<SUP>2+</SUP>]i) increase and intracellular reactive oxygen species concentration ([ROS]i) reduction in cells on TiO2nanotubes. UV photocatalysis-mediated [Ca<SUP>2+</SUP>]iincrease is dependent on extracellular and intracellular ROS generation. Furthermore, extracellular Ca<SUP>2+</SUP>influx through voltage-gated calcium channels (VGCCs) is critical for the UV photocatalysis-mediated [Ca<SUP>2+</SUP>]iincrease, while phospholipase C (PLC) activation is not required. Considering the physiological roles of Ca<SUP>2+</SUP>signaling in BMMs and osteoclastogenesis, nanotopography on the Ti surface should be considered an important factor that can influence successful dental implantation.</P>

Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCγ2-Ca²⁺ Signaling Pathway and Prevents Inflammation-Mediated Bone Loss

Kim, Ju-Young,Park, Sun-Hyang,Baek, Jong Min,Erkhembaatar, Munkhsoyol,Kim, Min Seuk,Yoon, Kwon-Ha,Oh, Jaemin,Lee, Myeung Su American Chemical Society and American Society of 2015 Journal of natural products Vol.78 No.9

<P>Harpagoside (HAR) is a natural compound isolated from <I>Harpagophytum procumbens</I> (devil’s claw) that is reported to have anti-inflammatory effects; however, these effects have not been investigated in the context of bone development. The current study describes for the first time that HAR inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis <I>in vitro</I> and suppresses inflammation-induced bone loss in a mouse model. HAR also inhibited the formation of osteoclasts from mouse bone marrow macrophages (BMMs) in a dose-dependent manner as well as the activity of mature osteoclasts, including filamentous actin (F-actin) ring formation and bone matrix breakdown. This involved a HAR-induced decrease in extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) phosphorylation, leading to the inhibition of Syk-Btk-PLCγ2-Ca<SUP>2+</SUP> in RANKL-dependent early signaling, as well as the activation of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which resulted in the down-regulation of various target genes. Consistent with these <I>in vitro</I> results, HAR blocked lipopolysaccharide (LPS)-induced bone loss in an inflammatory osteoporosis model. However, HAR did not prevent ovariectomy-mediated bone erosion in a postmenopausal osteoporosis model. These results suggest that HAR is a valuable agent against inflammation-related bone disorders but not osteoporosis induced by hormonal abnormalities.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jnprdf/2015/jnprdf.2015.78.issue-9/acs.jnatprod.5b00233/production/images/medium/np-2015-002336_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/np5b00233'>ACS Electronic Supporting Info</A></P>