Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis

Halasy-Nagy, Judit; Rodan, Gideon A.; Reszka, Alfred A.

doi:10.1016/s8756-3282(01)00615-9

Cited by 165 publications

(127 citation statements)

References 36 publications

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“…This inhibitor did not interfere with phosphorylation of Akt itself (Figure 5d). The concentration of Akt inhibitor used (10 mM) was two-fold above its IC 50 for suppression of Akt and eightfold below its IC 50 for PI3K, 45 suggesting that this response was relatively Akt specific. pp60 c-src activity may also play a role in this part of the pathway, since it is required for signaling from PI3K to S6K and from RANKL to Akt.…”

Section: Ocl Require Continuous Protein Translation For Survivalmentioning

confidence: 99%

“…Inhibition of MEK1/2 resulted in only partial reduction of S6 phosphorylation (Figure 5c and d). For inhibition of PI3K, we used LY294002 at a concentration of 5 mM, which is approximately three-fold above its IC 50 for PI3K and equal to its reported IC 50 for mTOR autokinase activity in vitro. 44 Suppression of cytokine-induced S6 phosphorylation by LY294002 was complete (Figure 5c), suggesting that PI3K inhibition played a prominent role in the effect.…”

Section: Ocl Require Continuous Protein Translation For Survivalmentioning

confidence: 99%

“…Time-course analyses revealed that little bone resorption takes place during the first 24 h of culture and that ALN effects are not seen until 48 h or more. 50 We therefore examined rapamycin effects at 72 and 96 h, where it was observed to reduce bone resorption significantly at all tested concentrations. During the first 72 h, dose-dependent inhibition of up to 60% was observed, with an IC 50 of 1-3 nM.…”

Section: Mtor/s6k Signaling Is Required For Ocl Survival and Functionmentioning

confidence: 99%

“…50 Briefly, cells were stained for TRAP in 50 mM sodium acetate (pH 5.0), 30 mM sodium tartrate, 0.1% Triton X-100 with 0.3 mg/ml fast red violet LB (Sigma, St. Louis, MO, USA) and 0.1 mg/ml naphthol AS-MX phosphate (Sigma). Actin and nuclei were stained with 5 U/ml TRITC or FITC-labeled phalloidin (Molecular Probes, Eugene, OR, USA) together with 50 mg/ml Hoechst 33342 dye (Molecular Probes).…”

Section: Histochemistrymentioning

confidence: 99%

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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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Section: Ocl Require Continuous Protein Translation For Survivalmentioning

confidence: 99%

Section: Ocl Require Continuous Protein Translation For Survivalmentioning

confidence: 99%

Section: Mtor/s6k Signaling Is Required For Ocl Survival and Functionmentioning

confidence: 99%

Section: Histochemistrymentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2003

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“…68 Briefly, cells were stained for TRAP in 50 mM sodium acetate (pH 5.0), 30 mM sodium tartrate, 0.1% Triton X-100 with 0.3 mg/ml fast red violet LB and 0.1 mg/ml naphthol AS-MX phosphate (both from Sigma). Actin and nuclei were stained with 5 U/ml TRITC or FITC-labeled phalloidin together with 50 mg/ ml Hoechst 33342 dye (both from Molecular Probes, Eugene, OR, USA) and mounted using antifade (Molecular Probes).…”

Section: Histochemistrymentioning

confidence: 99%

Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins

et al. 2004

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Osteoporosis is associated with both atherosclerosis and vascular calcification. No mechanism yet explains the parallel progression of these diseases. Here, we demonstrate that osteoclasts (OCL) depend on lipoproteins to modulate cellular cholesterol levels and that this controls OCL formation and survival. Removal of cholesterol in OCL via high-density lipoprotein or cyclodextrin treatment dose-dependently induced apoptosis, with actin disruption, nuclear condensation and caspase-3 activation. One mechanism linked to the induction of OCL apoptosis was the cell-type-specific failure to induce HMG-CoA reductase mRNA expression, suggesting an absence of feedback regulation of de novo cholesterol biosynthesis. Furthermore, cyclodextrin treatment substantially suppressed essential M-CSF and RANKL-induced survival signaling pathways via Akt, mTOR and S6K. Consistent with these findings, cholesterol delivery via lowdensity lipoprotein (LDL) significantly increased OCL viability. Interestingly, OCLs from the LDL receptor (LDLR)À/À mouse exhibited reduced size and lifespan in vitro. Remarkably, LDLR þ / þ OCL in lipoprotein-deficient medium phenocopied LDLRÀ/À OCL, while fusion and spreading of LDLRÀ/À OCL was rescued when cholesterol was chemically delivered during differentiation. With hyperlipidemia being associated with disease of the vascular system and bone, these findings provide novel insights into the selective lipoprotein and cholesterol dependency of the bone resorbing cell.

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Cellular mechanism of inhibition of osteoclastic resorption of bone and calcified cartilage by long‐term pamidronate administration in ovariectomized mature rats

Mayahara¹,

Sasaki²

2003

Anat. Rec.

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We examined the effects of long-term bisphosphonate (BP, pamidronate) administration at a therapeutic dose (1.5 mg/kg/day) on the distribution, structure, and vacuolar-type H ϩ -ATPase expression of osteoclasts, and the resulting trabecular bone volume and structure in ovariectomized (OVX) mature rats. Six-month-old female rats were allocated to sham-operated control, untreated-OVX, and BP-administered OVX groups. Postoperatively, BP was administered intraperitoneally once a day to OVX rats for up to 30 days. On postoperative days 14, 30, and 60, all of the rats were killed and the distal metaphyseal area of the dissected humeri was examined. Quantitative backscattered-electron image analysis revealed that the trabecular bone volume/ unit medullary area in untreated OVX rats was significantly (P Ͻ 0.05) lower than that in sham-operated controls at 30 and 60 days postoperation. BP administration significantly (P Ͻ 0.05) increased trabecular bone volume at 14, 30, and 60 days postoperation in BP-administered OVX rats compared to both sham-operated and untreated OVX rats. Compared to untreated OVX rats, the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts along the bone trabeculae in BP-administered OVX rats was not significantly decreased on days 14 and 30, but was significantly decreased on day 60. Ultrastructurally, BP administration caused the disappearance of both the ruffled border (RB) and the clear zone (CZ) structures, and decreased the expression of vacuolar-type H ϩ -ATPase in most osteoclasts, but did not significantly induce apoptosis of osteoclasts detected by the terminal dUTP nick end-labeling (TUNEL) method. Our results suggest that long-term BP administration significantly reduces bone and calcified cartilage resorption through impairment of the structure and bone-resorbing function of osteoclasts, and thereby effectively maintains trabecular bone volume and structure in ovariectomy-induced acute estrogen deficiency in mature rats. Anat Rec Part A 274A: 817-826, 2003.

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Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis

Cited by 165 publications

References 36 publications

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

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

Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins

Cellular mechanism of inhibition of osteoclastic resorption of bone and calcified cartilage by long‐term pamidronate administration in ovariectomized mature rats

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