• Title/Summary/Keyword: Bone biomolecules

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NDRG2 Expression Decreases Tumor-Induced Osteoclast Differentiation by Down-regulating ICAM1 in Breast Cancer Cells

  • Kim, Bomi;Nam, Sorim;Lim, Ji Hyun;Lim, Jong-Seok
    • Biomolecules & Therapeutics
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    • v.24 no.1
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    • pp.9-18
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    • 2016
  • Bone matrix is properly maintained by osteoclasts and osteoblasts. In the tumor microenvironment, osteoclasts are increasingly differentiated by the various ligands and cytokines secreted from the metastasized cancer cells at the bone metastasis niche. The activated osteoclasts generate osteolytic lesions. For this reason, studies focusing on the differentiation of osteoclasts are important to reduce bone destruction by tumor metastasis. The N-myc downstream-regulated gene 2 (NDRG2) has been known to contribute to the suppression of tumor growth and metastasis, but the precise role of NDRG2 in osteoclast differentiation induced by cancer cells has not been elucidated. In this study, we demonstrate that NDRG2 expression in breast cancer cells has an inhibitory effect on osteoclast differentiation. RAW 264.7 cells, which are monocytic preosteoclast cells, treated with the conditioned media (CM) of murine breast cancer cells (4T1) expressing NDRG2 are less differentiated into the multinucleated osteoclast-like cells than those treated with the CM of 4T1-WT or 4T1-mock cells. Interestingly, 4T1 cells stably expressing NDRG2 showed a decreased mRNA and protein level of intercellular adhesion molecule 1 (ICAM1), which is known to enhance osteoclast maturation. Osteoclast differentiation was also reduced by ICAM1 knockdown in 4T1 cells. In addition, blocking the interaction between soluble ICAM1 and ICAM1 receptors significantly decreased osteoclastogenesis of RAW 264.7 cells in the tumor environment. Collectively, these results suggest that the reduction of ICAM1 expression by NDRG2 in breast cancer cells decreases osteoclast differentiation, and demonstrate that excessive bone resorption could be inhibited via ICAM1 down-regulation by NDRG2 expression.

Isopsoralen Induces Differentiation of Prechondrogenic ATDC5 Cells via Activation of MAP Kinases and BMP-2 Signaling Pathways

  • Li, Liang;Eun, Jae-Soon;Nepal, Manoj;Ryu, Jae-Ha;Cho, Hyoung-Kwon;Choi, Bo-Yun;Soh, Yun-Jo
    • Biomolecules & Therapeutics
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    • v.20 no.3
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    • pp.299-305
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    • 2012
  • Endochondral bone formation is the process by which mesenchymal cells condense to become chondrocytes, which ultimately form new bone. The process of chondrogenic differentiation and hypertrophy is critical for bone formation and as such is regulated by many factors. In this study, we aimed to indentify novel factors that regulate chondrogenesis. We investigated the possible role of isopsoralen in induction of chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells. Isopsoralen treatment stimulated the accumulation of cartilage nodules in a dose-dependent manner. Further, ATDC5 cells treated with isopsoralen were stained more intensely with Alcian blue than control cells, suggesting that isopsoralen increases the synthesis of matrix proteoglycans. Similarly, isopsoralen markedly induced the activation of alkaline phosphatase activity compared with control cells. Isopsoralen enhanced the expressions of chondrogenic marker genes such as collagen II, collagen X, OCN, Smad4 and Sox9 in a time-dependent manner. Furthermore, isopsoralen induced the activation of extracellular signal-regulated kinase (ERK) and p38 MAP kinase, but not that of c-jun N-terminal kinase (JNK). Isopsoralen significantly enhanced the protein expression of BMP-2 in a time-dependent manner. PD98059 and SB 203580, inhibitors of ERK and p38 MAPK, respectively, decreased the number of stained cells treated with isopsoralen. Taken together, these results suggest that isopsoralen mediates a chondromodulating effect by BMP-2 or MAPK signaling pathways, and is therefore a possible therapeutic agent for bone growth disorders.

Hydroxychavicol Inhibits In Vitro Osteoclastogenesis via the Suppression of NF-κB Signaling Pathway

  • Sirada Srihirun;Satarat Mathithiphark;Chareerut Phruksaniyom;Pitchanun Kongphanich;Wisutthaporn Inthanop;Thanaporn Sriwantana;Salunya Tancharoen;Nathawut Sibmooh;Pornpun Vivithanaporn
    • Biomolecules & Therapeutics
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    • v.32 no.2
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    • pp.205-213
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    • 2024
  • Hydroxychavicol, a primary active phenolic compound of betel leaves, previously inhibited bone loss in vivo by stimulating osteogenesis. However, the effect of hydroxychavicol on bone remodeling induced by osteoclasts is unknown. In this study, the anti-osteoclastogenic effects of hydroxychavicol and its mechanism were investigated in receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclasts. Hydroxychavicol reduced the number of tartrate resistance acid phosphatase (TRAP)-positive multinucleated, F-actin ring formation and bone-resorbing activity of osteoclasts differentiated from RAW264.7 cells in a concentration-dependent manner. Furthermore, hydroxychavicol decreased the expression of osteoclast-specific genes, including cathepsin K, MMP-9, and dendritic cell-specific transmembrane protein (DC-STAMP). For mechanistic studies, hydroxychavicol suppressed RANKL-induced expression of major transcription factors, including the nuclear factor of activated T-cells 1 (NFATc1), c-Fos, and c-Jun. At the early stage of osteoclast differentiation, hydroxychavicol blocked the phosphorylation of NF-κB subunits (p65 and Iκβα). This blockade led to the decrease of nuclear translocation of p65 induced by RANKL. In addition, the anti-osteoclastogenic effect of hydroxychavicol was confirmed by the inhibition of TRAP-positive multinucleated differentiation from human peripheral mononuclear cells (PBMCs). In conclusion, hydroxychavicol inhibits osteoclastogenesis by abrogating RANKL-induced NFATc1 expression by suppressing the NF-κB signaling pathway in vitro.

Distribution and Excretion of Radioactivity Following Intraportal Administration of $^{166}$ 7Ho-Chitosan Complex to Rats (흰쥐의 간문맥으로 투여한 $_{166}$ Holmium-chitosan의 분포와 배설)

  • BAEK, Min Sun;PARK, Kyung Bae;KIM, Dong Hyun
    • Biomolecules & Therapeutics
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    • v.5 no.3
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    • pp.233-238
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    • 1997
  • The distribution and excretion of radioactivity were examined after intraportal administration of sup 166/Ho-chitosan complex at a dose of 1 mcitg (10 mg chitosan/kg) to rats. Whole body macroautoluminographs showed that the radioactivity after an administration was concentrated in liver and perfused primarily to organs including kidney, spleen, and bone marrow, then to muscle and brain. Similar profiles were observed from 2 hr to 168 hr after the administration. The relative percentage of radioactivity in bone and spinal column increased with time, suggesting that free $^{166}$ Ho, released from chitosan complex deposited in the liver, selectively binds to these tissues. $^{166}$ Ho-chitosan complex administered intraportally was excreted less than 4% through urine (2.7$\pm$0.8%) and feces (0.65 $\pm$ 0.4%) up to seven days. These results demonstrate that the radio-activity of $_{166}$ Ho-chitusan complex when administered intraportally, mainly localizes in liver without affec-ting other tissues and organs. Considering the short half life of $^{166}$ Ho and the localization to the liver, $^{166}$ Ho-chitosan complex might be a useful agent in the treatment of hepatic carcinoma.

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Natural Products as Sources of Novel Drug Candidates for the Pharmacological Management of Osteoarthritis: A Narrative Review

  • Kang, Young-Hoon;Lee, Hyun Jae;Lee, Choong Jae;Park, Jin-Sung
    • Biomolecules & Therapeutics
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    • v.27 no.6
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    • pp.503-513
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    • 2019
  • Osteoarthritis is a chronic degenerative articular disorder. Formation of bone spurs, synovial inflammation, loss of cartilage, and underlying bone restructuring have been reported to be the main pathologic characteristics of osteoarthritis symptoms. The onset and progression of osteoarthritis are attributed to various inflammatory cytokines in joint tissues and fluids that are produced by chondrocytes and/or interact with chondrocytes, as well as to low-grade inflammation in intra-articular tissues. Disruption of the equilibrium between the synthesis and degradation of the cartilage of the joint is the major cause of osteoarthritis. Hence, developing a promising pharmacological tool to restore the equilibrium between the synthesis and degradation of osteoarthritic joint cartilage can be a useful strategy for effectively managing osteoarthritis. In this review, we provide an overview of the research results pertaining to the search for a novel candidate agent for osteoarthritis management via restoration of the equilibrium between cartilage synthesis and degradation. We especially focused on investigations of medicinal plants and natural products derived from them to shed light on the potential pharmacotherapy of osteoarthritis.

Recent Advances of Therapeutic Targets for the Treatment of Periodontal Disease

  • Kim, Woo Jin;Soh, Yunjo;Heo, Seok-Mo
    • Biomolecules & Therapeutics
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    • v.29 no.3
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    • pp.263-267
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    • 2021
  • Periodontal disease is primarily associated with bacterial infection such as dental plaque. Dental plaque, an oral biofilm harboring a complex microbial community, can cause various inflammatory reactions in periodontal tissue. In many cases, the local bacterial invasion and host-mediated immune responses lead to severe alveolar bone destruction. To date, plaque control, non-surgical, and surgical interventions have been the conventional periodontal treatment modalities. Although adjuvant therapies including antibiotics or supplements have accompanied these procedures, their usage has been limited by antibiotic resistance, as well as their partial effectiveness. Therefore, new strategies are needed to control local inflammation in the periodontium and host immune responses. In recent years, target molecules that modulate microbial signaling mechanisms, host inflammatory substances, and bone immune responses have received considerable attention by researchers. In this review, we introduce three approaches that suggest a way forward for the development of new treatments for periodontal disease; (1) quorum quenching using quorum sensing inhibitors, (2) inflammasome targeting, and (3) use of FDA-approved anabolic agents, including Teriparatide and sclerostin antibody.

Aloe-Emodin Induces Chondrogenic Differentiation of ATDC5 Cells via MAP Kinases and BMP-2 Signaling Pathways

  • Yang, Ming;Li, Liang;Heo, Seok-Mo;Soh, Yunjo
    • Biomolecules & Therapeutics
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    • v.24 no.4
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    • pp.395-401
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    • 2016
  • Endochondral bone formation is the process by which mesenchymal cells condense into chondrocytes, which are ultimately responsible for new bone formation. The processes of chondrogenic differentiation and hypertrophy are critical for bone formation and are therefore highly regulated. The present study was designed to investigate the effect of aloe-emodin on chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells. Aloe-emodin treatment stimulated the accumulation of cartilage nodules in a dose-dependent manner. ATDC5 cells were treated with aloe-emodin and stained with alcian blue. Compared with the control cells, the ATDC5 cells showed more intense alcian blue staining. This finding suggested that aloe-emodin induced the synthesis of matrix proteoglycans and increased the activity of alkaline phosphatase. Aloe-emodin also enhanced the expressions of chondrogenic marker genes such as collagen II, collagen X, BSP and RunX2 in a time-dependent manner. Furthermore, examination of the MAPK signaling pathway showed that aloe-emodin increased the activation of extracellular signal-regulated kinase (ERK), but had no effect on p38 and c-jun N-terminal kinase (JNK). Aloe-emodin also enhanced the protein expression of BMP-2 in a time-dependent manner. Thus, these results showed that aloe-emodin exhibited chodromodulating effects via the BMP-2 or ERK signaling pathway. Aloe-emodin may have potential future applications for the treatment of growth disorders.

A Comparison of ROCK Inhibitors on Human Bone Marrow-Derived Mesenchymal Stem Cell Differentiation into Neuron-Like Cells

  • Lee, Hyun-Sun;Kim, Kwang-Sei;O, Eun-Ju;Joe, Young-Ae
    • Biomolecules & Therapeutics
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    • v.18 no.4
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    • pp.386-395
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    • 2010
  • Bone marrow-derived mesenchymal stem cells (BM-MSC) are a multipotent cell population that can differentiate into neuron-like cells. Previously it has been reported that murine BM-MSC can differentiate into neuron-like cells by co-treatment with a Rho-associated kinase (ROCK) inhibitor -Y27632 and $CoCl_2$. In this study, we compared several ROCK inhibitors for the ability to induce human BM-MSCs to differentiate into neuron-like cells in the presence of $CoCl_2$. Y27632 with high specificity for ROCK at 1-30 ${\mu}M$ was best at inducing neuronal differentiation of MSCs. Compared to HA1077 and H1152, which also effectively induced morphological change into neuron-like cells, Y27632 showed less toxicity even at 100 ${\mu}M$, and resulted in longer multiple branching processes at a wide range of concentrations at 6 h and 72 h post-induction. H89, however, which has less specificity by inhibition of protein kinase A, S6 kinase 1 and MSK1 with similar or greater potency, was less effective at inducing neuronal differentiation of MSCs. Simvastatin, which can inhibit Rho, Ras, and Rac by blocking the synthesis of isoprenoid intermediates, showed little activity for inducing morphological changes of MSCs into neuron-like cells. Accordingly, the expression patterns for neuronal cell markers,including ${\beta}$-tubulin III, neuron-specific enolase, neurofilament, and microtubule-associated protein, were consistent with the pattern of the morphological changes. The data suggest that the ROCK inhibitors with higher specificity are more effective at inducing neuronal differentiation of MSCs.

WIN-34B May Have Analgesic and Anti-Inflammatory Effects by Reducing the Production of Pro-Inflammatory Mediators in Cells via Inhibition of IκB Signaling Pathways

  • Kim, Kyoung-Soo;Choi, Hyun-Mi;Yang, Hyung-In;Yoo, Myung-Chul
    • Biomolecules & Therapeutics
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    • v.20 no.1
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    • pp.50-56
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    • 2012
  • WIN-34B showed analgesic and anti-inflammatory effects in various animal models of pain and osteoarthritis. However, the molecular mechanism by which WIN-34B inhibits pain and inflammation in vivo remains to be elucidated. We investigated the molecular mechanisms of the actions of WIN-34B using various in vitro models using fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA FLSs), RAW264.7 cells and peritoneal macrophages. WIN-34B inhibited the level of IL-6, $PGE_2$, and MMP-13 in IL-$1{\beta}$-stimulated RA FLSs in a dose-dependent manner. The mRNA levels were also inhibited by WIN-34B. The level of $PGE_2$, NO, IL-$1{\beta}$, and TNF-${\alpha}$ were inhibited by WIN-34B at different concentrations in LPS-stimulated RAW264.7 cells. The production of NO and $PGE_2$ was inhibited by WIN-34B in a dose-dependent manner in LPS-stimulated peritoneal macrophages. All of these effects were comparable to the positive control, celecoxib or indomethacin. I${\kappa}B$B signaling pathways were inhibited by WIN-34B, and the migration of NF-${\kappa}B$ into the nucleus was inhibited, which is consistent with the degradation of $I{\kappa}B-{\alpha}$. Taken together, the results suggest that WIN-34B has potential as a therapeutic drug to reduce pain and inflammation by inhibiting the production of pro-inflammatory mediators.

Effects of Ginsenosides Rg1 on Osteoblasts Cultured with Ti Particles

  • Lin, Yu;Wu, Yinsheng;He, Jiacheng;Huang, Yunmei;Lin, Yanping
    • Biomolecules & Therapeutics
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    • v.20 no.1
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    • pp.75-80
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    • 2012
  • The aim of this study was to explore the role and effect of ginsenosides Rg1 on osteoblasts cultured with Ti particles. Osteoblasts from neonatal rats were cultured with particles and different doses of Rg1, the main active ingredient in ginsenosides Rg1. We found that the COX-2, $PGE_2$, TNF-${\alpha}$, IL-1, and IL -6 concentrations in the medium of cells cultured with Ti particles significantly increased as compared with that of the control cells (p<0.05 or p<0.01). In addition, cells cultured with Ti particles alone exhibited the highest concentrations of these molecules. The $PGE_2$, TNF-${\alpha}$, IL-1, and IL-6 levels in the medium of cells cultured with Rg1 were in between those of the control cells and the cells cultured with Ti particles alone. The IL-1ra level in the group cultured with Ti and medium-dose Rg1 was the highest followed by the cells cultured with Ti and high-dose Rg1 and those cultured with Ti and low-dose Rg1 (p<0.05). In conclusion, ginsenosides can reduce the levels of infl ammatory cytokines produced by osteoblasts on induction with Ti particles and can prevent prosthesis loosening.