The alteration of osteoclast morphology by diphosphonates in bone organ culture

Rowe, Erin; Hausmann, Ernest

doi:10.1007/bf02546397

Cited by 69 publications

(20 citation statements)

References 15 publications

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“…It follows from this that P-C-P may inhibit bone resorption by directly increasing the resistance of the mineral phase of bone to degradation (16). However, the inhibition of resorption by P-C-P is also associated with dramatic changes in both osteoclast morphology and in the size of the osteoclast population (2)(3)(4)17), indicating that these compounds exert a profound effect upon resorbing cells as well as upon the bone mineral.…”

Section: Resultsmentioning

confidence: 92%

Differential Action of the Bisphosphonates (3-Amino-1-Hydroxypropylidene)-1,1-Bisphosphonate (APD) and Disodium Dichloromethylidene Bisphosphonate (Cl2MDP) on Rat Macrophage-mediated Bone Resorption In Vitro

Teitelbaum²,

et al. 1982

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A B S T R A C T The bisphosphonates (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) and disodium dichloromethylidene bisphosphonate (Cl2MDP) effectively inhibit the accelerated bone resorption associated with some skeletal disorders, e.g., Paget's disease. However, it has not been established whether these compounds exert their inhibitory effect by rendering the bone mineral more resistant to degradation, by diminishing the activity of resorbing cells, or through some combination of both activities. In this study, we have tested these possibilities using an in vitro resorption assay system consisting of elicited rat peritoneal macrophages co-cultured with particles of 45Ca-labeled, devitalized rat bone. This assay system permits the quantitative assessment of the action of APD and Cl2MDP on the two major phases of bone resorption (cell-substrate attachment and osteolysis) under circumstances where the drugs are present continuously or, most importantly for the issues in question, after the separate pretreatment of the particles or the resorbing cells.Our data indicate that (a) Both APD and C12MDP at concentrations 25 X 106 M diminish macrophagemediated 45Ca release (i.e., bone resorption) in a log Received for publication 22 dose-dependent fashion. (b) A 10-min pretreatment of bone particles with either bisphosphonate (P-C-P) similarly inhibits resorptive activity, but is most pronounced with Cl2MDP. However, only APD is effective in reducing resorption when cells are preincubated (for 24 h) with P-C-P. (c) In cultures containing both labeled and unlabeled bone, significant inhibition occurs only when the labeled particles are coated with P-C-P (indicating that the action of P-C-P-treated bone is highly localized). (d) P-C-P does not diminish cell-bone particle attachment, an essential step in the resorptive process. On the other hand, delaying the addition of P-C-P until after cell-bone attachment is completed significantly reduces the resorption-inhibiting effect of these compounds. (e) C12MDP reduces culture DNA content in proportion to its inhibitory effect on resorption, and both the inhibitory and cytotoxic actions of this P-C-P are dependent upon the presence of bone. On the other hand, APD is cytotoxic only at very high concentrations (10-4 M), acts independently of the presence of bone, and inhibits resorption without killing cells.We conclude that the mechanisms of action of APD and C12MDP are markedly different. C12MDP is a potent cytotoxin in the presence of bone and apparently exerts its inhibitory effect in this manner. APD is noncytotoxic at levels adequate to suppress resorption and, therefore, must inhibit macrophage activity by some other mechanism. Neither P-C-P appears to limit resorption by decreasing the solubility of mineralized bone matrix.J. Clin. Invest.

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Section: Resultsmentioning

confidence: 92%

Differential Action of the Bisphosphonates (3-Amino-1-Hydroxypropylidene)-1,1-Bisphosphonate (APD) and Disodium Dichloromethylidene Bisphosphonate (Cl2MDP) on Rat Macrophage-mediated Bone Resorption In Vitro

Teitelbaum²,

et al. 1982

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“…It is assumed (but by no means proven) that the sensitivity of the osteoclasts to PTH is reduced by EHDP. Rowe and Hausmann [15] studied the effect of E H D P on osteoclasts in tissue culture and concluded in favor of a direct, non-specific toxic effect of E H D P on these cells.…”

Section: Discussionmentioning

confidence: 98%

“…The osteoclasts, too, became atypical after a certain period of drug administration, with an increased number of nuclei and marked vacuolization. Cellular conglomerations also have been reported [6,15].…”

Section: Introductionmentioning

confidence: 91%

Influence of a diphosphonate on the cellular aspect of young bone tissue

Ph²,

Kuijpers

et al. 1980

Calcif Tissue Int

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Stimulated by the rather sparse information in the literature on cellular changes induced by EHDP, we carried out electron microscopic investigations on young bone tissue and on de novo bone formation. Cellular changes could be observed during continuous administration of EHDP. The osteoblasts demonstrated temporary storing of crystalloid structures in the mitochondria, and atypical osteocytes showed persistent changes indicative of hyperactivity. The osteoclasts exhibited varying ultrastructural features with respect to the number and appearance of nuclei, Golgi, RER, and lysosomes. These changes under the influence of EHDP could be an indication of altered activity of the osteoclast. The possible interference of EHDP with bone cell metabolism is discussed.

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“…Bisphosphonates, including two that are metabolized by Dictyostelium (Cl2MBP and F2MBP), are inhibitors of osteoclastmediated bone resorption and have been shown to have cytotoxic and antiproliferative effects on mammalian cells such as osteoclasts, macrophages and connective tissue cells (Rowe and Hausmann, 1976;Fast et al, 1978;Rowe and Hays, 1983;Stevenson and Stevenson, 1986;Cecchini et al, 1987;Flanagan and Chambers, 1989;Van Rooijen and Kors, 1989;Carano et al, 1990). As bisphosphonates appear to have cellular targets that are common to both osteoclasts and Dictyostelium , it is possible that those of low potency such as C12MBP affect mammalian cells, including osteoclasts, by inhibiting aminoacyl-tRNA synthetases or by incorporation into nucleotide analogues.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of bisphosphonates into adenine nucleotides by amoebae of the cellular slime mould Dictyostelium discoideum

Rogers

Russell

et al. 1994

Biochemical Journal

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Bisphosphonates are a class of synthetic pyrophosphate analogues. Some are known to be potent inhibitors of osteoclast-mediated bone resorption in vivo, but their mechanisms of action are unclear. The order of potency of bisphosphonates as inhibitors of bone resorption closely matches the order of potency as inhibitors of growth of amoebae of the slime mould Dictyostelium discoideum, indicating that bisphosphonates may have a mechanism of action that is similar in both osteoclasts and Dictyostelium. Methylenebisphosphonate and several halogenated derivatives, which have low potency as antiresorptive agents and as growth inhibitors of Dictyostelium, are metabolized intracellularly by Dictyostelium amoebae into methylene-containing adenine nucleotides. We have used a combination of n.m.r. and f.p.l.c. analysis to determine whether incorporation into nucleotides is a feature of other bisphosphonates, especially those that are potent antiresorptive agents. Only bisphosphonates with short side chains or of low potency are incorporated into adenine nucleotides, whereas those with long side chains or of high potency are not metabolized. Bisphosphonate metabolism in cell-free extracts of Dictyostelium was accompanied by inhibition of aminoacylation of tRNA by several aminoacyl-tRNA synthetases. These enzymes were barely affected by the bisphosphonates that were not metabolized. The results indicate that some bisphosphonates are not metabolically inert analogues of pyrophosphate and appear to be metabolized by aminoacyl-tRNA synthetases. The cellular effects of some bisphosphonates may be the result of their incorporation into adenine nucleotides or inhibition of aminoacyl-tRNA synthetases, although the potent bisphosphonates appear to act by a different mechanism.

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The alteration of osteoclast morphology by diphosphonates in bone organ culture

Cited by 69 publications

References 15 publications

Differential Action of the Bisphosphonates (3-Amino-1-Hydroxypropylidene)-1,1-Bisphosphonate (APD) and Disodium Dichloromethylidene Bisphosphonate (Cl2MDP) on Rat Macrophage-mediated Bone Resorption In Vitro

Differential Action of the Bisphosphonates (3-Amino-1-Hydroxypropylidene)-1,1-Bisphosphonate (APD) and Disodium Dichloromethylidene Bisphosphonate (Cl2MDP) on Rat Macrophage-mediated Bone Resorption In Vitro

Influence of a diphosphonate on the cellular aspect of young bone tissue

Incorporation of bisphosphonates into adenine nucleotides by amoebae of the cellular slime mould Dictyostelium discoideum

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