Convergent signaling by acidosis and receptor activator of NF-κB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts

Komarova, Svetlana V.; Pereverzev, Alexey; Shum, Jonathan; Sims, Stephen M.; Dixon, S. Jeffrey

doi:10.1073/pnas.0406874102

Cited by 156 publications

(142 citation statements)

References 38 publications

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“…It is now well established that NFATc1 is a master regulator of osteoclast differentiation (8,9,27,28). In addition to its role during the early commitment of monocytic precursors to osteoclast differentiation, accumulating data support the importance of NFATc1 during later stages of osteoclast maturation, such as cell-cell fusion; this transcription factor regulates the expression of various genes that encode proteins involved in osteoclast fusion, including Atp6v0d2 and DC-STAMP (4), and osteoclast-mediated bone resorption, such as TRAP, cathepsin K, c-Src, and ␤3 integrin (8,9,27,28).…”

Section: Discussionmentioning

confidence: 99%

“…For example, NFATc1-null cells do not differentiate into osteoclasts and overexpression of intact NFATc1 stimulates osteoclast development from monocyte lineage precursors in a RANKL-independent manner (8). In addition to its important role in osteoclast differentiation, NFATc1 appears to be involved in bone resorption by osteoclasts (9). Recently, we reported a novel role for NFATc1 as a positive regulator of RANKL-mediated osteoclast fusion; this effect occurs as a result of the direct up-regulation of the expression of the fusion-regulating molecules Atp6v0d2 and DC-STAMP (10).…”

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confidence: 99%

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The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation

Lee

Kim

Jeong

et al. 2008

Journal of Biological Chemistry

102

108

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A spontaneous mutation in Bruton's tyrosine kinase (Btk) induces a defect in B-cell development that results in the immunodeficiency diseases X-linked agammaglobulinemia in humans and X-linked immunodeficiency (Xid) in mice. Here we show an unexpected role of Btk in osteoclast formation. When bone marrow cells derived from Xid mice were stimulated with receptor activator of NF-B ligand, an osteoclast differentiation factor, they did not completely differentiate into mature multinucleated osteoclasts. Moreover, we found that the defects appeared to occur at the stage in which mononuclear preosteoclasts fuse to generate multinucleated cells. Supporting this notion, macrophages from Xid mice also failed to form multinucleated foreign body giant cells. The fusion defect of the Xid mutant osteoclasts was caused by decreased expression of nuclear factor of activated T cells c1 (NFATc1), a master regulator of osteoclast differentiation, as well as reduced expression of various osteoclast fusion-related molecules, such as the d2 isoform of vacuolar H ؉ -ATPase V0 domain and the dendritic cell-specific transmembrane protein. This deficiency was completely rescued by the introduction of a constitutively active form of NFATc1 into bone marrow-derived macrophages. Our data provide strong evidence that Btk plays a critical role in osteoclast multinucleation by modulating the activity of NFATc1.The processes underlying bone remodeling, which are dependent on a balance between osteoblast-driven bone formation and osteoclast-mediated bone resorption, control homeostasis in the skeletal system (1, 2). For efficient bone resorption, the fusion of mononuclear preosteoclasts from the myeloid lineage is critical for the formation of functional multinucleated osteoclasts (2-5). Recently, it was reported that mice genetically deficient for dendritic cell-specific transmembrane protein (DC-STAMP) or the d2 isoform of the vacuolar H ϩ -ATPase V0 domain (Atp6v0d2) exhibit osteopetrotic phenotypes due to defects in osteoclast fusion during osteoclastogenesis (4, 5). Interestingly, these studies also showed that cellcell fusion is essential for the formation of giant macrophages (4, 5).In concert with macrophage colony-stimulating factor (M-CSF), 3 receptor activator of NF-B ligand (RANKL), a member of the tumor necrosis factor superfamily, regulates the differentiation of osteoclasts as well as cell survival, fusion, and activation (3, 6, 7). The binding of RANKL to receptor activator of NF-B induces the expression of transcription factors, including NFATc1, NF-B, c-Fos, Mitf, and PU.1; these transcription factors have been shown to be important for osteoclastogenesis in vitro and in vivo (2, 3, 6). For example, NFATc1-null cells do not differentiate into osteoclasts and overexpression of intact NFATc1 stimulates osteoclast development from monocyte lineage precursors in a RANKL-independent manner (8). In addition to its important role in osteoclast differentiation, NFATc1 appears to be involved in bone resorption by osteoclasts (9). Rece...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation

Lee

Kim

Jeong

et al. 2008

Journal of Biological Chemistry

102

108

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“…44,45,48 This notion is consistent with previous studies in which an upregulated HO system suppressed immune/inflammatory responses by abolishing macrophage infiltration and reducing mast-cell and basophils histamine release. 45 Given that NF-kB is activated by PLC, 15,16 and PLC mobilizes intracellular calcium to elevate blood pressure 11 and stimulate inflammation, 48 upregulating the HO system would be beneficial in these conditions. Figure 5 The effects of the CO-releasing molecule, CORM-3, on cGMP, ET-1, NF-kB, PLC, IP 3 and resting intracellular calcium in the mesenteric arterioles of UnX-DOCA-salt hypertensive rats.…”

Section: Discussionmentioning

confidence: 99%

“…As UnX-DOCA hypertension is characterized by elevated ET-1, and ET-1 stimulates PLC and IP 3 , 14 which in turn activate NF-kB, 15,16 the concomitant suppression of ET-1, PLC, IP 3 , 8-isoprostane and NF-kB by heme-arginate may be explored to attenuate the oxidative/inflammatory destruction of tissues. Collectively, our study unveils the effects of heme-arginate on PLC activity, and highlights the important link between the HO system, ET-1, the PLC-IP 3 signaling and NF-kB.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Moreover, in DOCA hypertension, the high levels of the synthetic mineralcorticoid would further potentiate vascular contractility through stimulation of PLC and diacylglycerol. 12,13 As UnX-DOCA hypertension is characterized by elevated ET-1, and ET-1 stimulates PLC and IP 3 , 14 which in turn activates nuclear-factor kB (NF-kB), 15,16 ET-1, PLC, IP 3 , 8-isoprostane and NF-kB may constitute a potent oxidative/inflammatory destructive axis. Interestingly, NF-kB activates heme-oxygenase (HO-1) by binding to the promoter region of HO-1 gene.…”

Section: Introductionmentioning

confidence: 99%

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Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

Ndisang

Jadhav

2010

Hypertens Res

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Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP 3 ) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volumeoverload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCAsalt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme-arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor jB (NF-jB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP 3 and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP 3 and NF-jB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP 3 -NF-jB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP 3 , which in turn activates NF-jB, the concomitant reduction of ET-1, PLC, IP 3 and NF-jB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate.

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Free Radicals, Signal Transduction, and Human Disease

Jomová

Valko

2011

Oxidative Stress in Vertebrates and Invertebrates

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Convergent signaling by acidosis and receptor activator of NF-κB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts

Cited by 156 publications

References 38 publications

The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation

The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation

Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

Free Radicals, Signal Transduction, and Human Disease

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