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1.
Curr Pharm Des ; 16(27): 2950-60, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20722616

RESUMO

Bisphosphonates are widely used in the treatment of diseases involving excessive bone resorption, such as osteoporosis, cancer-associated bone disease, and Paget's disease of bone. They target to the skeleton due to their calcium-chelating properties, where they primarily act by inhibiting osteoclast-mediated bone resorption. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolised to cytotoxic ATP analogues, while the more potent, nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase, thereby preventing the prenylation of small GTPases that are necessary for the normal function and survival of osteoclasts. In recent years, these concepts have been refined, with an increased understanding of the exact mode of inhibition of FPP synthase and the consequences of inhibiting this enzyme. Recent studies further suggest that the R2 side chain, as well as determining the potency for inhibiting the target enzyme FPP synthase, also influences bone mineral binding, which may influence distribution within bone and duration of action. While bisphosphonates primarily affect the function of resorbing osteoclasts, it is becoming increasingly clear that bisphosphonates may also target the osteocyte network and prevent osteocyte apoptosis, which could contribute to their anti-fracture effects. Furthermore, increasing evidence implicates monocytes and macrophages as direct targets of bisphosphonate action, which may explain the acute phase response and the anti-tumour activity in certain animal models. Bone mineral affinity is likely to influence the extent of any such effects of these agents on non-osteoclast cells. While alternative anti-resorptive therapeutics are becoming available for clinical use, bisphosphonates currently remain the principle drugs used to treat excessive bone resorption.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Osso e Ossos/efeitos dos fármacos , Difosfonatos/farmacologia , Desenho de Fármacos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Animais , Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/farmacocinética , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/metabolismo , Cálcio/metabolismo , Quelantes/metabolismo , Quelantes/farmacocinética , Quelantes/farmacologia , Quelantes/uso terapêutico , Difosfonatos/metabolismo , Difosfonatos/farmacocinética , Difosfonatos/uso terapêutico , Humanos , Macrófagos/metabolismo , Monócitos/metabolismo , Especificidade de Órgãos , Distribuição Tecidual
2.
Calcif Tissue Int ; 80(2): 132-6, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17308995

RESUMO

Mature osteoclasts and their precursors are notoriously difficult to transfect using nonviral approaches, a limitation that represents a major technical obstacle in the study of osteoclast biology. Here, we describe a simple electroporation method using Amaxa Nucleofector technology that results in efficient transfection of human blood-derived osteoclast precursors, which can be differentiated in subsequent culture to generate mature osteoclasts that retain expression of the transgene. Moreover, since these osteoclasts maintain the ability to resorb dentine, this technique could prove useful for assessing the role of specific genes/proteins in osteoclast function.


Assuntos
Osteoclastos/citologia , Transfecção/métodos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Sobrevivência Celular , Células Cultivadas , Eletroporação/métodos , Engenharia Genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Osteoclastos/metabolismo , Ligante RANK/farmacologia
3.
Calcif Tissue Int ; 72(1): 80-4, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12370802

RESUMO

The Ras superfamily of small GTP-binding proteins (also known as small GTPases) comprises more than 80 highly conserved proteins of the Ras, Rho, and Rab subfamilies that are involved in multiple intracellular signalling pathways. These proteins are able to function as molecular switches in the transduction of signals from membrane receptors by cycling between an inactive, GDP-bound state and an active, GTP-bound state, which can then interact with a number of different effector molecules (Fig. 1). The activity of small GTPases is regulated by three classes of regulatory proteins: guanine nucleotide exchange factors (GEFs), which catalyse the exchange of GDP for GTP, thereby activating the small GTPase; GTPase-activating proteins (GAPs), which enhance the intrinsic ability of small GTPases to hydrolyse GTP, resulting in reversion to the inactive GDP-bound state; and guanine nucleotide dissociation inhibitors (GDIs), which preferentially bind to the GDP-bound GTPases in the cytoplasm, thereby inhibiting the release of GDP and maintaining the GTPase in the inactive state [1]. GDIs have not been identified for all small GTPases, but play an important role in the control of the Rho family GTPases.


Assuntos
Proteínas Monoméricas de Ligação ao GTP/metabolismo , Osteoclastos/enzimologia , Prenilação de Proteína/fisiologia , Animais , Humanos , Transdução de Sinais
4.
J Biol Chem ; 276(51): 48213-22, 2001 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-11581260

RESUMO

Nitrogen-containing bisphosphonate drugs inhibit bone resorption by inhibiting FPP synthase and thereby preventing the synthesis of isoprenoid lipids required for protein prenylation in bone-resorbing osteoclasts. NE10790 is a phosphonocarboxylate analogue of the potent bisphosphonate risedronate and is a weak anti-resorptive agent. Although NE10790 was a poor inhibitor of FPP synthase, it did inhibit prenylation in J774 macrophages and osteoclasts, but only of proteins of molecular mass approximately 22-26 kDa, the prenylation of which was not affected by peptidomimetic inhibitors of either farnesyl transferase (FTI-277) or geranylgeranyl transferase I (GGTI-298). These 22-26-kDa proteins were shown to be geranylgeranylated by labelling J774 cells with [(3)H]geranylgeraniol. Furthermore, NE10790 inhibited incorporation of [(14)C]mevalonic acid into Rab6, but not into H-Ras or Rap1, proteins that are modified by FTase and GGTase I, respectively. These data demonstrate that NE10790 selectively prevents Rab prenylation in intact cells. In accord, NE10790 inhibited the activity of recombinant Rab GGTase in vitro, but did not affect the activity of recombinant FTase or GGTase I. NE10790 therefore appears to be the first specific inhibitor of Rab GGTase to be identified. In contrast to risedronate, NE10790 inhibited bone resorption in vitro without markedly affecting osteoclast number or the F-actin "ring" structure in polarized osteoclasts. However, NE10790 did alter osteoclast morphology, causing the formation of large intracellular vacuoles and protrusion of the basolateral membrane into large, "domed" structures that lacked microvilli. The anti-resorptive activity of NE10790 is thus likely due to disruption of Rab-dependent intracellular membrane trafficking in osteoclasts.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Difosfonatos/farmacologia , Inibidores Enzimáticos/farmacologia , Macrófagos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Prenilação de Proteína , Piridinas/farmacologia , Animais , Linhagem Celular , Macrófagos/metabolismo , Microscopia Eletrônica , Osteoclastos/metabolismo , Osteoclastos/ultraestrutura , Coelhos
5.
J Pharmacol Exp Ther ; 296(2): 235-42, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11160603

RESUMO

It has long been known that small changes to the structure of the R(2) side chain of nitrogen-containing bisphosphonates can dramatically affect their potency for inhibiting bone resorption in vitro and in vivo, although the reason for these differences in antiresorptive potency have not been explained at the level of a pharmacological target. Recently, several nitrogen-containing bisphosphonates were found to inhibit osteoclast-mediated bone resorption in vitro by inhibiting farnesyl diphosphate synthase, thereby preventing protein prenylation in osteoclasts. In this study, we examined the potency of a wider range of nitrogen-containing bisphosphonates, including the highly potent, heterocycle-containing zoledronic acid and minodronate (YM-529). We found a clear correlation between the ability to inhibit farnesyl diphosphate synthase in vitro, to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro, and to inhibit bone resorption in vivo. The activity of recombinant human farnesyl diphosphate synthase was inhibited at concentrations > or = 1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximately equal to minodronate > risedronate > ibandronate > incadronate > alendronate > pamidronate) closely matching the order of antiresorptive potency. Furthermore, minor changes to the structure of the R(2) side chain of heterocycle-containing bisphosphonates, giving rise to less potent inhibitors of bone resorption in vivo, also caused a reduction in potency up to approximately 300-fold for inhibition of farnesyl diphosphate synthase in vitro. These data indicate that farnesyl diphosphate synthase is the major pharmacological target of these drugs in vivo, and that small changes to the structure of the R(2) side chain alter antiresorptive potency by affecting the ability to inhibit farnesyl diphosphate synthase.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Reabsorção Óssea/prevenção & controle , Difosfonatos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos de Nitrogênio/farmacologia , Alquil e Aril Transferases/metabolismo , Animais , Difosfonatos/química , Inibidores Enzimáticos/química , Geraniltranstransferase , Indicadores e Reagentes , Ácido Mevalônico/metabolismo , Compostos de Nitrogênio/química , Osteoclastos/metabolismo , Conformação Proteica , Prenilação de Proteína , Coelhos , Proteínas Recombinantes/química , Relação Estrutura-Atividade
6.
J Bone Miner Res ; 15(8): 1467-76, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10934645

RESUMO

Bisphosphonates are the important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Although their molecular mechanism of action has not been fully elucidated, recent studies have shown that the nitrogen-containing bisphosphonates can inhibit protein prenylation in macrophages in vitro. In this study, we show that the nitrogen-containing bisphosphonates risedronate, zoledronate, ibandronate, alendronate, and pamidronate (but not the non nitrogen-containing bisphosphonates clodronate, etidronate, and tiludronate) prevent the incorporation of [14C]mevalonate into prenylated (farnesylated and geranylgeranylated) proteins in purified rabbit osteoclasts. The inhibitory effect of nitrogen-containing bisphosphonates on bone resorption is likely to result largely from the loss of geranylgeranylated proteins rather than loss of farnesylated proteins in osteoclasts, because concentrations of GGTI-298 (a specific inhibitor of geranylgeranyl transferase I) that inhibited protein geranylgeranylation in purified rabbit osteoclasts prevented osteoclast formation in murine bone marrow cultures, disrupted the osteoclast cytoskeleton, inhibited bone resorption, and induced apoptosis in isolated chick and rabbit osteoclasts in vitro. By contrast, concentrations of FTI-277 (a specific inhibitor of farnesyl transferase) that prevented protein farnesylation in purified rabbit osteoclasts had little effect on osteoclast morphology or apoptosis and did not inhibit bone resorption. These results therefore show the molecular mechanism of action of nitrogen-containing bisphosphonate drugs in osteoclasts and highlight the fundamental importance of geranylgeranylated proteins in osteoclast formation and function.


Assuntos
Benzamidas/farmacologia , Difosfonatos/farmacologia , Inibidores Enzimáticos/farmacologia , Osteoclastos/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Reabsorção Óssea , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Citoesqueleto/efeitos dos fármacos , Metionina/análogos & derivados , Metionina/farmacologia , Camundongos , Osteoclastos/metabolismo , Osteoclastos/fisiologia , Coelhos
7.
Cancer ; 88(12 Suppl): 2961-78, 2000 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-10898340

RESUMO

BACKGROUND: Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. METHODS: This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts. RESULTS: Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases. CONCLUSIONS: Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear.


Assuntos
Difosfonatos/farmacologia , Animais , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Difosfonatos/farmacocinética , Humanos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Proteínas Tirosina Fosfatases/antagonistas & inibidores , ATPases Translocadoras de Prótons/antagonistas & inibidores , Relação Estrutura-Atividade
8.
J Bone Miner Res ; 14 Suppl 2: 53-65, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10510215

RESUMO

Bisphosphonates are chemically stable analogs of inorganic pyrophosphate, which are resistant to breakdown by enzymatic hydrolysis. The biological effects of bisphosphonates on calcium metabolism were originally ascribed to their physico-chemical effects on hydroxyapatite crystals. Although such effects may contribute to their overall action, their effects on cells are probably of greater importance, particularly for the more potent compounds. Remarkable progress has been made in increasing the potency of bisphosphonates as inhibitors of bone resorption, and the most potent compounds in current use are characterized by the presence of a nitrogen atom at critical positions in the side chain which, together with the bisphosphonate moiety itself, seems to be essential for maximal activity. As a class the bisphosphonates offer a very effective means of treating Paget's disease.


Assuntos
Doenças Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Animais , Reabsorção Óssea , Células Cultivadas , Humanos , Modelos Químicos
10.
J Bone Miner Res ; 13(11): 1668-78, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9797474

RESUMO

Recent evidence suggests that bisphosphonates (BPs) may inhibit bone resorption by mechanisms that lead to osteoclast apoptosis. We have previously shown that BPs also reduce cell viability and induce apoptosis in the macrophage-like cell line J774. To determine whether BPs inhibit osteoclast-mediated bone resorption and affect J774 macrophages by the same molecular mechanism, we examined the potency to reduce J774 cell viability of pairs of nitrogen-containing BPs that differ slightly in the structure of the heterocycle-containing side chain but that differ markedly in antiresorptive potency. In all cases, the most potent antiresorptive BP of each pair also caused the greatest loss of J774 viability, while the less potent antiresorptive BPs were also less potent at reducing J774 cell viability. Similarly, the bisphosphinate, phosphonoalkylphosphinate and monophosphonate analogs of BPs (in which one or both phosphonate groups are modified, giving rise to much less potent or inactive antiresorptive agents) were much less potent or inactive at reducing J774 cell viability. Thus, the structure-activity relationships of BPs for inhibiting bone resorption match those for causing loss of cell viability in J774 cells, indicating that BPs inhibit osteoclast-mediated bone resorption and reduce J774 macrophage viability by the same molecular mechanism. Loss of J774 cell viability after treatment with BPs was associated with a parallel increase in apoptotic cell death. We have recently proposed that nitrogen-containing BPs reduce cell viability and cause J774 apoptosis as a consequence of inhibition of enzymes of the mevalonate pathway and hence loss of prenylated proteins. In this study, the BPs that were potent inducers of J774 apoptosis and potent antiresorptive agents were also found to be effective inhibitors of protein prenylation in J774 macrophages, whereas the less potent BP analogs did not inhibit protein prenylation. This provides strong evidence that BPs with a heterocyclic, nitrogen-containing side chain, such as risedronate, inhibit osteoclast-mediated bone resorption and induce J774 apoptosis by preventing protein prenylation.


Assuntos
Apoptose/efeitos dos fármacos , Reabsorção Óssea , Difosfonatos/farmacologia , Macrófagos/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Animais , Núcleo Celular/efeitos dos fármacos , Células Cultivadas , DNA/metabolismo , Fragmentação do DNA , Difosfonatos/química , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Microscopia de Fluorescência , Relação Estrutura-Atividade
11.
Mol Pharmacol ; 54(4): 631-8, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9765505

RESUMO

The exact mechanisms of action of antiresorptive bisphosphonate drugs remain unclear, although they may inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. These drugs also cause apoptosis in J774 macrophages, probably as a consequence of inhibition of protein prenylation. However, the molecular pathways that lead to apoptosis are not known. In some cells, apoptosis induced by statins (other inhibitors of protein prenylation) is dependent on protein synthesis. The aim of this study was to further characterize the kinetics and biochemical features of bisphosphonate-induced apoptosis, including the dependence on protein synthesis. Alendronate-induced apoptosis in J774 cells occurred after approximately 16 hr of treatment, although shorter exposures to the drug followed by incubation in bisphosphonate-free medium also committed cells to apoptosis. The appearance of apoptotic cells was associated with the appearance of caspase-3-like activity. Apoptosis induced by bisphosphonate or mevastatin was found to be dependent on protein synthesis because cycloheximide inhibited chromatin condensation, DNA fragmentation and activation of caspase-3-like protease or proteases. Protein synthesis was required for events that lead to commitment to apoptosis but not for the execution phase because cycloheximide did not prevent apoptosis when added >/=15 hr after the start of alendronate treatment. Furthermore, staurosporine-induced caspase-3-like activity and apoptosis in J774 cells could not be prevented by cycloheximide. These observations demonstrate that activation of caspase-3-like proteases and inhibition of commitment to apoptosis by cycloheximide are common features of apoptotic cell death induced by inhibitors of protein prenylation such as bisphosphonates.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caspases/metabolismo , Difosfonatos/farmacologia , Macrófagos/efeitos dos fármacos , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/farmacologia , Alendronato/farmacologia , Animais , Radioisótopos de Carbono , Caspase 3 , Linhagem Celular , Cicloeximida/farmacologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Lovastatina/análogos & derivados , Lovastatina/farmacologia , Macrófagos/citologia , Macrófagos/metabolismo , Ácido Mevalônico/análogos & derivados , Ácido Mevalônico/metabolismo , Camundongos
12.
J Bone Miner Res ; 13(4): 581-9, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9556058

RESUMO

Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of metabolic bone diseases. Although the molecular targets of bisphosphonates have not been identified, these compounds inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. Bisphosphonates also induce apoptosis in mouse J774 macrophages in vitro, probably by the same mechanisms that lead to osteoclast apoptosis. We have found that, in J774 macrophages, nitrogen-containing bisphosphonates (such as alendronate, ibandronate, and risedronate) inhibit post-translational modification (prenylation) of proteins, including the GTP-binding protein Ras, with farnesyl or geranylgeranyl isoprenoid groups. Clodronate did not inhibit protein prenylation. Mevastatin, an inhibitor of 3-hydroxy-3-methylglutatyl (HMG)-CoA reductase and hence the biosynthetic pathway required for the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, also caused apoptosis in J774 macrophages and murine osteoclasts in vitro. Furthermore, alendronate-induced apoptosis, like mevastatin-induced apoptosis, could be suppressed in J774 cells by the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, while the effect of alendronate on osteoclast number and bone resorption in murine calvariae in vitro could be overcome by the addition of mevalonic acid. These observations suggest that nitrogen-containing bisphosphonate drugs cause apoptosis following inhibition of post-translational prenylation of proteins such as Ras. It is likely that these potent antiresorptive bisphosphonates also inhibit bone resorption by preventing protein prenylation in osteoclasts and that enzymes of the mevalonate pathway or prenyl protein transferases are the molecular targets of the nitrogen-containing bisphosphonates. Furthermore, the data support the view that clodronate acts by a different mechanism.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Difosfonatos/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas ras/metabolismo , Alendronato/antagonistas & inibidores , Alendronato/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Ácido Clodrônico/farmacologia , Inibidores Enzimáticos/farmacologia , Ácido Etidrônico/análogos & derivados , Ácido Etidrônico/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Hidroximetilglutaril-CoA-Redutases NADP-Dependentes , Ácido Ibandrônico , Lovastatina/análogos & derivados , Lovastatina/farmacologia , Macrófagos/efeitos dos fármacos , Ácido Mevalônico/metabolismo , Camundongos , Osteoclastos/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Ácido Risedrônico , Relação Estrutura-Atividade , Proteínas ras/química
13.
J Bone Miner Res ; 11(10): 1482-91, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8889848

RESUMO

Bisphosphonates (BPs) are an important class of antiresorptive drugs used in the treatment of bone diseases, including osteoporosis. Although their mechanism of action has not been identified at the molecular level, there is substantial evidence that BPs can have a direct effect on osteoclasts by mechanisms that may lead to osteoclast cell death by apoptosis. BPs can also inhibit proliferation and cause cell death in macrophages in vitro. We have now shown that the toxic effect of BPs on macrophages is also due to the induction of apoptotic, rather than necrotic, cell death. Morphological and biochemical features that are definitive of apoptosis (chromatin condensation, nuclear fragmentation, and endonuclease-mediated internucleosomal cleavage of DNA) could be identified in mouse macrophage-like J774 and RAW264 cells, following treatment with 100 microM pamidronate, alendronate, and ibandronate for 24 h or more. Clodronate was much less potent, even at 2000 microM, while 2000 microM etidronate did not cause apoptosis. Apoptosis was not due to increased synthesis of nitric oxide and could not be prevented by inhibitors of nitric oxide synthases. Since macrophages, like osteoclasts, are particularly susceptible to BPs, these observations support the recent suggestion that the mechanism by which BPs inhibit bone resorption may involve osteoclast apoptosis. Furthermore, the macrophage-like cell lines used in this study may be a convenient model with which to identify the molecular mechanisms by which BPs promote apoptosis in osteoclasts. Induction of macrophage apoptosis by BPs in vivo may also account, at least in part, for the anti-inflammatory properties of BPs as well as the ability of BPs to cause an acute phase response.


Assuntos
Alendronato/toxicidade , Apoptose/efeitos dos fármacos , Difosfonatos/toxicidade , Macrófagos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Animais , Medula Óssea/metabolismo , Células da Medula Óssea , Reabsorção Óssea , Divisão Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Células Cultivadas , DNA/metabolismo , Fragmentação do DNA , Eletroforese em Gel de Poliacrilamida , Ácido Ibandrônico , Macrófagos/citologia , Camundongos , Necrose , Pamidronato , Biossíntese de Proteínas
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