Immortalization of osteoclast precursors by targeting Bcl -XL and Simian virus 40 large T antigen to the osteoclast lineage in transgenic mice.

Hentunen, Teuvo; Reddy, Sakamuri V.; Boyce, Brendan F.; Devlin, Rowena D.; Park, H.-R.; Chung, Habong; Selander, Katri S.; Dallas, Mark; Kurihara, Noriyoshi; Galson, Deborah L.; Goldring, Steven R.; Koop, Barbara A.; Windle, Jolene J.; Roodman, G. David

doi:10.1172/jci2004

Cited by 50 publications

(36 citation statements)

References 28 publications

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“…We have focused on Bcl-xL in the current study because its role in osteoclast survival has been repeatedly documented (12,14,17,37). In addition, we found that TNF stimulates expression of Bcl-xL, but not the other Bcl-2 family members we tested ( Figure 5).…”

Section: Discussionmentioning

confidence: 78%

“…Macrophage colony-stimulating factor (M-CSF), a key survival factor for cells in the myeloid lineage, stimulates Bcl-xL expression (11,12). Osteoclasts generated from bone marrow cells of transgenic mice that overexpress Bcl-xL under the control of the tartrate-resistant acid phosphatase (TRAP) promoter are more resistant to serum withdrawal-induced cell death (13,14), demonstrating that Bcl-xL is involved in the control of osteoclast apoptosis.…”

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confidence: 99%

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Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

et al. 2005

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Objective. To investigate why bisphosphonates are less effective at preventing focal bone loss in rheumatoid arthritis (RA) patients than in those with generalized osteoporosis, and the mechanisms involved.Methods. The response of osteoclasts to alendronate (ALN) in tumor necrosis factor-transgenic (TNFTg) mice that develop erosive arthritis and in wild-type littermates was studied. TNF-Tg and wild-type mice were given ALN, and the osteoclast numbers in the inflamed joints and in the long bones were compared. The expression levels of Bcl-xL in the osteoclasts of TNF-Tg and wild-type mice were examined by immunostaining. The effect of overexpression of Bcl-xL and Ets-2 proteins on ALN-induced osteoclast apoptosis was determined using an in vitro osteoclast survival assay and retrovirus transfer approach.Results. ALN reduced osteoclast numbers in the metaphyses by 97%, but by only 46% in the adjacent inflamed joints. Bcl-xL expression was markedly higher in osteoclasts in the joints than in those in the metaphyses of TNF-Tg mice. Bcl-xL or Ets-2 overexpression protected osteoclasts from ALN-induced apoptosis, and TNF stimulated Bcl-xL and Ets-2 expression in osteoclasts. Overexpression of Ets-2 increased Bcl-xL messenger RNA in osteoclasts, while a dominant-negative form of the Ets-2 blocked the protective effect of Bcl-xL or TNF on ALN-induced apoptosis.Conclusion. The reduced efficacy of bisphosphonates to stop bone erosion in the inflamed joints of RA patients may result from local high levels of TNF up-regulating Ets-2 expression in osteoclasts, which in turn stimulates Bcl-xL expression in them and reduces their susceptibility to bisphosphonate-induced apoptosis.

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

et al. 2005

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“…59 Taken together, we can conclude that tight control of translation seems to be necessary to provide BCL-2-like proteins and prolong Ocl survival. 60,61 Identification of responsible candidate proteins is the subject of further research. In summary, we describe for the first time a shared role for mTOR/S6K in the prosurvival signaling of osteoclastogenic cytokines.…”

Section: Discussionmentioning

confidence: 99%

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

et al. 2003

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Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFa, activates NF-jB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin (mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF-and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.

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“…109 The generation of TRAP transgenic mice expressing the SV40 large T antigen, with or without the bcl-XL antiapoptotic gene, did not transform cells outside the osteoclast lineage. 14,54 The TRAP promoter has also been used to target overexpression of the c-fos gene to osteoclasts to generate a mouse model with some characteristics of Paget's disease. 11 Although Langerhans cells in the skin express TRAP, 49 the gene is also expressed in keratinocytes, and was shown to be elevated in the transgenic animals.…”

Section: Trap Expression At Extraskeletal Sitesmentioning

confidence: 99%

Structure, function, and regulation of tartrate-resistant acid phosphatase

Oddie

Schenk

Angel

et al. 2000

Bone

200

198

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Immortalization of osteoclast precursors by targeting Bcl -XL and Simian virus 40 large T antigen to the osteoclast lineage in transgenic mice.

Cited by 50 publications

References 28 publications

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

Structure, function, and regulation of tartrate-resistant acid phosphatase

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