Bisphosphonates act on osteoblastic cells and inhibit osteoclast formation in mouse marrow cultures

Nishikawa, Manabu; Akatsu, Takuhiko; Katayama, Yasuyuki; Yasutomo, Y.; Kado, Sarah Y.; Kugai, Nobuo; Yamamoto, Michiko; Nagata, Noriko

doi:10.1016/8756-3282(95)00426-2

Cited by 156 publications

(105 citation statements)

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“…They also shorten osteoclast lifespan by induction of programmed cell death (apoptosis) (Hughes et al, 1995). In addition, the inhibitory activity of bisphosphonates on bone resorption may be indirectly mediated by other cells such as cells of the osteoblastic lineage or the macrophage family (Sahni et al, 1993;Nishikawa et al, 1996;Vitte et al, 1996;Siwek et al, 1997;Fromigue and Body, 2002). On the other hand, we and others (Fromigue et al, 2000;Senaratne et al, 2000;Jagdev et al, 2001b) previously showed that bisphosphonates can induce human breast cancer cell death in vitro (apoptosis and/or necrosis), which could contribute to their beneficial clinical effects.…”

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confidence: 98%

“…Bisphosphonates are very stable compounds that exhibit a high affinity for calcified matrices such as hydroxyapatite in bone (Lin, 1996), and are successfully used as powerful inhibitors of increased bone resorption in several bone diseases (Fleisch, 1997a, b). They act by decreasing the recruitment, proliferation and differentiation of preosteoclasts (Lowik et al, 1988;Hughes et al, 1989;Nishikawa et al, 1996), their adhesion to the mineralised matrix and, most importantly, the resorptive activity of mature osteoclasts (Sato et al, 1991;Selander et al, 1994;Azuma et al, 1995;Murakami et al, 1995). They also shorten osteoclast lifespan by induction of programmed cell death (apoptosis) (Hughes et al, 1995).…”

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confidence: 99%

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Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

2003

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Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone -derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.

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confidence: 98%

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confidence: 99%

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

2003

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“…In this way, knowledge of osteoclast activity inhibitors [33][34][35] has led some authors to suggest that indirect action of bisphosphonates on resorption would not be exerted through the inhibition of resorption-stimulating osteoblastic factor secretion, but rather by stimulating the secretion of resorption-inhibiting factors. In this regard, Nishikawa et al [36] and Vitte´et al [13] demonstrated that bisphosphonates stimulate secretion of osteoclastinhibiting molecules by osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Alendronate and Etidronate do not Regulate Interleukin 6 and 11 Synthesis in Normal Human Osteoblasts in Culture

Engel

Serrano

Mariñoso

et al. 2003

Calcified Tissue International

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Abstract. Bisphosphonates exert a potent inhibitory effect on bone resorption. Several studies have been performed, with contradictory results, to ascertain whether the effect of bisphosphonates on osteoclasts could be produced, at least in part, by modulation of the synthesis of resorption-promoting factors by osteoblasts. The aim of this study was to evaluate the effect of etidronate (10 )4 -10 )9 M) and alendronate (10 )7 -10 )12 M) on the production of IL-6 and IL-11 using human osteoblast cultures. Cytokines were quantified by ELI-SA, and mRNA expression was tested. Treatment with alendronate and etidronate had no effect on the synthesis of IL-6 or IL-11, and IL-6 and IL-11 mRNA levels. These results were obtained both in nonstimulated cultures and in cultures stimulated by means of TNF-a, IL-1b, and TNF-a+IL-1b, with or without FCS. In conclusion, a possible indirect osteoclast-mediated effect of alendronate and etidronate on bone resorption would not be exerted through reduction in osteoblastic synthesis of IL-6 and IL-11.Key words: Alendronate -Etidronate -Human osteoblasts -Interleukin 6 -Interleukin 11Bisphosphonates are potent inhibitors of bone resorption when tested in different systems, both in vivo and in vitro. At present, there are two models that would explain how this inhibition is produced. On the one hand, owing to the high affinity of bisphosphonates for hydroxyapatite, the inhibiting effect of these bone matrix-linked compounds would result from their direct action on the resorptive ability of osteoclasts [1][2][3]. Thanks to their endocytotic capacity osteoclasts would internalize bisphosphonates, which in turn would inhibit the metabolic reactions involved in osteoclast function. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogs of ATP. It is likely that intracellular accumulation of these metabolites inhibits osteoclast function.The more potent, nitrogen-containing bisphosphonates (such as pamidronate and ibandronate) are not metabolized but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isopropenoid compounds that are essential for posttranslational modification of small GTPases. These GTPases are important signaling proteins regulating a variety of cell processes required to maintain osteoclast activity and survival [4]. Loss of osteoclast function and apoptosis is probably the consequence of function loss of one or more of these signaling proteins [5][6][7][8].On the other hand, several in vitro studies [9, 10] failed to show the differences in inhibitory power on bone resorption found in vivo among the different types of bisphosphonates. These differences appeared when osteoclasts were co-cultured with osteoblasts [11]. This finding suggests that the effect of bisphosphonates on osteoclasts could be produced, at least in part, by modulation of the synthesis of resorption-promoting [12] or resorption-inhibiting factors by osteoblasts [13].Among t...

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“…Numerous studies suggest suggest direct anticancer effect of bisphosphonates even in the bone microenvironment. The positive effects of bisphosphonate on bone health in vivo is due to their ability to disrupt or alter paracrine interactions in the bone microevironment (37,38). The evidence for this includes observations that bisphosphonates reduce IL-6 expression by osteoblasts (39) and induce soluble inhibitors of osteoclast activity into conditioned media (40).…”

Section: Mechanism Of Apoptotic Deathmentioning

confidence: 99%

Antitumor Effects of Aminobisphosphonates on Renal Cell Carcinoma Cell Lines

et al. 2006

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PurposeBisphosphonates are established as a supportive therapy for a number of malignancies which metastasise to bone. Previous reports also suggest potent antitumour and antiangiogenic properties. We investigated the in vitro activity of two aminobisphosphonates, pamidronate (PAM) and zoledronic acid (ZOL) on the growth and survival of three renal cell carcinoma cell lines (Caki-2, 769-P and D69581). Experimental design

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Bisphosphonates act on osteoblastic cells and inhibit osteoclast formation in mouse marrow cultures

Cited by 156 publications

References 23 publications

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

Alendronate and Etidronate do not Regulate Interleukin 6 and 11 Synthesis in Normal Human Osteoblasts in Culture

Antitumor Effects of Aminobisphosphonates on Renal Cell Carcinoma Cell Lines

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