Proteasome inhibitors induce osteoclast survival by activating the Akt pathway

Kwak, Han Bok; Lee, Myeung Su; Kim, Hun Soo; Cho, Hae Joong; Kim, Jeung Woo; Lee, Zang Hee; Oh, Jae‐Min

doi:10.1016/j.bbrc.2008.05.048

Cited by 20 publications

(17 citation statements)

References 36 publications

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“…The discrepancy between the results obtained with ATA and AG490 could be based on different intervention in additional signaling pathways distinct from JAK-STAT signaling, which are in fact described in other cell models (Tsi et al, 2002;Kwak et al, 2008). However, the involvement of STAT1 in doxorubicin-mediated gene regulation was further evidenced by silencing STAT1 expression using a specific siRNA, resulting in a strong reduction of doxorubicin induced gene regulation.…”

Section: Discussionmentioning

confidence: 88%

Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

Hußner¹,

Ameling²,

Hammer³

et al. 2012

Molecular Pharmacology

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Section: Discussionmentioning

confidence: 88%

Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

Hußner¹,

Ameling²,

Hammer³

et al. 2012

Molecular Pharmacology

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“…Akt/PKB regulates the survival of both osteoblasts 35 and osteoclasts. 36,37 In conclusion, Akt/PKB-dependent regulation of GSK3 participates in the control of renal tubular phosphate transport. Loss of Akt/PKB-dependent inhibition of GSK3␣␤ leads to renal phosphate wasting, which presumably contributes to or even accounts for the decrease of PTH release with resulting calciuria, decreased formation of 1,25-(OH) 2 D 3 , and decreased mineralization of bone.…”

Section: Discussionmentioning

confidence: 93%

PKB/SGK-Resistant GSK3 Enhances Phosphaturia and Calciuria

Föller¹,

Kempe²,

Boini

et al. 2011

Journal of the American Society of Nephrology

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Insulin and IGF1-dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase (PKB/SGK), which together phosphorylate and inactivate glycogen synthase kinase GSK3. Because insulin and IGF1 increase renal tubular calcium and phosphorus reabsorption, we examined GSK3 regulation of phosphate transporter activity and determined whether PKB/SGK inactivates GSK3 to enhance renal phosphate and calcium transport. Overexpression of GSK3 and the phosphate transporter NaPi-IIa in Xenopus oocytes decreased electrogenic phosphate transport compared with NaPi-IIaexpressing oocytes. PKB/SGK serine phosphorylation sites in GSK3 were mutated to alanine to create gsk3 KI mice resistant to PKB/SGK inactivation. Compared with wildtype animals, gsk3 KI animals exhibited greater urinary phosphate and calcium clearances with higher excretion rates and lower plasma concentrations. Isolated brush border membranes from gsk3 KI mice showed less sodium-dependent phosphate transport and Na-phosphate co-transporter expression. Parathyroid hormone, 1,25-OH vitamin D levels, and bone mineral density were decreased in gsk3 KI mice, suggesting a global dysregulation of bone mineral metabolism. Taken together, PKB/SGK phosphorylation of GSK3 increases phosphate transporter activity and reduces renal calcium and phosphate loss. The kidneys play a central role in the regulation of mineral homeostasis by mediating excretion or reabsorption, respectively, of phosphate, calcium, and magnesium. Phosphate reabsorption occurs in the proximal tubule and is mediated by at least three distinct sodium-dependent phosphate cotransporters, namely NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2), located in the apical brush border membrane. 1-3 Renal phosphate reabsorption is regulated by various factors including dietary phosphate intake, acid-base status, and various hormones, such as parathyroid hormone (PTH), 1,25-(OH) 2 vitamin D 3 , fibroblast growth factor 23, insulin, and insulin-like growth factor 1 (IGF1). 4 -10 Active calcium reabsorption is mediated by the transient receptor potential channel V5 (TRPV5) calcium channel expressed in the luminal membrane of the distal convoluted tubule and connecting tubule. [11][12][13] The expression and activity of TRPV5 is regulated by several factors similarly regulating renal phosphate transport, such as dietary calcium intake, PTH, klotho, ac-

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“…BMMs were transduced with the adenoviral vectors Ax1w1 (control) or AxMEK CA carrying CA-MEK1 (Ser 218 and Ser222 to Glu) as described previously [29]. …”

Section: Methodsmentioning

confidence: 99%

Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis

et al. 2017

Self Cite

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BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.MethodsBone marrow-derived macrophages and CD4+ T cells were isolated from wild-type (WT), Cxcl10 –/–, and Cxcr3 –/– mice. CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA. Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice. Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry. Serum was used to assess bone turnover and levels of osteoclastogenic cytokines.ResultsCXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation. Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4+ T cells. Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10-induced RANKL expression. In vivo, F4/80+ macrophages and CD4+ T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10 –/– and Cxcr3 –/– mice. Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis.ConclusionThese findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1353-6) contains supplementary material, which is available to authorized users.

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Proteasome inhibitors induce osteoclast survival by activating the Akt pathway

Cited by 20 publications

References 36 publications

Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

Regulation of Interferon-Inducible Proteins by Doxorubicin via Interferon γ-Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling in Tumor Cells

PKB/SGK-Resistant GSK3 Enhances Phosphaturia and Calciuria

Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis

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