Thapsigargin Modulates Osteoclastogenesis Through the Regulation of RANKL-Induced Signaling Pathways and Reactive Oxygen Species Production

Yip, Kirk H. M.; Zheng, Minghao; Steer, James H.; Giardina, Tindaro; Han, Renzhi; Lo, Susan; Bakker, Anthony J.; Cassady, A. I.; Joyce, David A.; Xu, Jiake

doi:10.1359/jbmr.050324

Cited by 77 publications

(70 citation statements)

References 49 publications

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“…Consistent with the observations, studies have demonstrated that DOX-mediated ROS production is reduced by the treatment of endothelial cells and H9c2 cells with an intracellular Ca 2+ chelator BAPTA (Kalivendi et al, 2001;2005). The increase of ROS generation is also observed in cardiomyocytes or spleen cells by treatment with Ca 2+ ionophore A23187 (Przygodzki et al, 2005) or thapsigargin (Yip et al, 2005), respectively. In addition, antioxidant properties of Ca 2+ channel blockers have been observed with in vivo and in vitro studies (Buyukokuroglu et al, 2001;Umemoto et al, 2004;Ysunari et al, 2005).…”

Section: Discussionsupporting

confidence: 78%

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

Kim

Kim²,

Kim³

et al. 2006

Exp Mol Med

228

134

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Section: Discussionsupporting

confidence: 78%

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

Kim

Kim²,

Kim³

et al. 2006

Exp Mol Med

228

134

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“…[6][7][8] A series of recent reports have indicated that reactive oxygen species (ROS) play a critical role in osteoclast differentiation initiated by RANK-RANKL signals. [9][10][11][12][13] It has been already reported that several of the intracellular signals essential for osteoclast formation, including NFκB, c-Jun aminoterminal kinase, PI3-kinase, and p38 MAPK, are sensitive to ROS. [9][10][11] Osteoclast formation has been shown to depend on NFκB activation.…”

Section: Yudoh Et Al Dovepressmentioning

confidence: 99%

“…[9][10][11] Osteoclast formation has been shown to depend on NFκB activation. 7,9,13 It has been demonstrated that NFκB is a target for cellular activation by ROS 9,12 and that antioxidants suppress NFκB activation in osteoclasts. [13][14][15] Recent studies have clearly revealed that ROS mediates RANK-RANKL signaling in osteoclastogenesis.…”

Section: Yudoh Et Al Dovepressmentioning

confidence: 99%

Water-soluble fullerene (C60) inhibits the osteoclast differentiation and bone destruction in arthritis

Yudoh

Karasawa²,

Masuko³

et al. 2009

IJN

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Abstract:Recently, it has been demonstrated that oxygen free radicals have an important role as a signaling messenger in the receptor activator NFκB (RANK) signal pathway required for osteoclast differentiation. The aim of this study was to examine the potential of a strong freeradical scavenger, water-soluble fullerene (C60), as a protective agent against the RANK-induced osteoclastogenesis and osteoclastic bone destruction in arthritis, both in vitro and in vivo. The effects of C60 on the RANK-induced osteoclastogenesis and osteoclastic bone resorption were examined in vitro. Adjuvant-induced arthritic rats were used as an animal model of arthritis. Rats were divided into two subgroups: control and treatment with C60 at 1.0 µM. The left ankle joint was injected intra-articularly with water-soluble C60 (20 µl) in the C60-treated group, while, as a control, the left ankle joint in the control rats received phosphate-buffered saline (20 µl) once weekly for eight weeks. Ankle joint tissues were prepared for histologic analysis. C60 significantly inhibited the responses of osteoclast precursor cells to RANK ligand, including osteoclast differentiation and osteoclastic bone resorption in vitro. In adjuvant-induced arthritic rats, intra-articular treatment with C60 in vivo reduced the number of osteoclasts and alleviated bone resorption and destruction in the joints, while control ankle joints showed progression of joint destruction with time. These findings indicate that C60 downregulates the RANK-induced osteoclast differentiation and is a potential therapeutic agent for inhibition of osteoclastic bone destruction in arthritis.

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“…To determine the effect of p62 wild-type and its UBA deletion mutant on RANKL-induced activation of NF-B and NFAT, RAW264.7 cells (5 ϫ 10 6 ) stably expressing EYFP-p62WT and EYFP-p62⌬UBA were transiently transfected with luciferase reporter construct 3 kb-Luc-SV40 as previously described 23,24 or with the luciferase reporter construct pNFAT-TA-Luc (BD Biosciences, San Jose, CA). Cells were plated in 24-well plates at a density of 1 ϫ 10 5 cells/well and treated with RANKL.…”

Section: Luciferase Reporter Gene Assay For the Nf-b And Nfat Activatmentioning

confidence: 99%

“…The importance of RANKL-induced activation on the cascades of mitogen-activated protein kinases, including extracellular signal-regulated kinase (ERK), in osteoclast differentiation and survival has been well documented. 24,27 To characterize better the involvement of p62 and its UBA domain in RANKL-signaling pathways and osteoclastogenesis, the role of p62WT and p62⌬UBA in RANKL-induced ERK phosphorylation was examined. Western blot analysis was performed using a specific antibody to the phosphorylated forms of ERK (ERK1/2).…”

Section: Overexpression Of Uba Domain Deletion Mutant Enhances Rankl-mentioning

confidence: 99%

p62 Ubiquitin Binding-Associated Domain Mediated the Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclast Formation

Yip

Feng

Pavlos

et al. 2006

The American Journal of Pathology

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Paget's disease of bone (PDB) is a debilitating bone disorder characterized by giant osteoclasts, enhanced bone destruction, and irregular bone formation. Recently, mutations in SQSTM1 (also known as p62) have been detected in PDB sufferers, with all mutations resulting in either loss of function or truncation/deletion of the ubiquitin binding-associated (UBA) domain. We hypothesized that mutation in the p62 gene resulting in either deletion or premature termination of the UBA domain accounts for the elevated osteoclastic formation and bone resorption associated with PDB. Remarkably, overexpression of the p62 UBA domain deletion mutant (p62⌬UBA) significantly enhanced osteoclastogenesis in vitro compared to cells expressing either wild-type p62 (p62WT) or a control vector in a RAW264.7 osteoclastogenic system. Overexpression of p62⌬UBA potentiated the formation of abnormally large multinucleated osteoclasts and resorption of bone, reminiscent of PDB. Consistent with the enhancement of osteoclastogenesis, overexpression of p62⌬UBA potentiated receptor activator of nuclear factor-B ligandinduced activation of nuclear factor-B, NFAT, and ERK phosphorylation. Paget's disease of bone (PDB) is a chronic focal skeletal disorder that is characterized by excessive osteoclast formation and activity followed by irregular new bone formation. The pathogenesis of PDB is thought to be initiated by the formation of giant osteoclasts followed by the deposition of primitive coarse-fibered bone in discontinuous trabeculae with a disjointed lamellar pattern. Although the precise etiology of PDB is presently unknown, several factors, including paramyxoviral infection and putative genetic factors are thought to contribute to its progression.

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Thapsigargin Modulates Osteoclastogenesis Through the Regulation of RANKL-Induced Signaling Pathways and Reactive Oxygen Species Production

Cited by 77 publications

References 49 publications

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

Water-soluble fullerene (C60) inhibits the osteoclast differentiation and bone destruction in arthritis

p62 Ubiquitin Binding-Associated Domain Mediated the Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclast Formation

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