A possible mechanism of the specific action of bisphosphonates on osteoclasts: Tiludronate preferentially affects polarized osteoclasts having ruffled borders

Murakami, Hiroshi; Takahashi, Naoyuki; Sasaki, Takahísa; Udagawa, Nobuyuki; Tanaka, Sakae; Nakamura, Ichiro; Zhang, D.; Barbier, A.; Suda, Toshio

doi:10.1016/s8756-3282(95)00150-6

Cited by 199 publications

(134 citation statements)

References 29 publications

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“…In vivo, bisphosphonates inhibit bone resorption both in normal animals as well as in animals in which bone resorption is stimulated experimentally (17). These findings led to bisphosphonates being used for the treatment of diseases such as osteoporosis and Paget's disease (18). Bisphosphonates were subsequently found to be useful for the treatment of malignant osteolysis.…”

Section: Discussionmentioning

confidence: 99%

Effect of YM529 on a Model of Mandibular Invasion by Oral Squamous Cell Carcinoma in Mice

Cui

Nomura²,

Noma³

et al. 2005

Clinical Cancer Research

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Purpose:This study examined the mechanisms of osteoclast-mediated bone invasion in a model of oral squamous cell carcinoma (OSCC). C3H/HeN mice were inoculated with SCC VII cells into the masseter region to establish an animal model of mandibular invasion by OSCC. Experimental Design:The mice were divided into three groups: a control group, given daily s.c. injections of saline; group 1, given 2 Ag per mouse per day of the bisphosphonate YM529; and group 2, given 10 Ag per mouse per day of YM529. After 3 weeks of treatment, the lesions were studied by micro-computed tomography. After tartrate-resistant acid phosphatase (TRAP) staining, the osteoclasts were easily identified, and the percentages of the area occupied by osteoclasts were calculated by computer for each sample. The tumors were analyzed by RT-PCR to determine the mRNA expression of interleukin-6 (IL-6), parathyroid hormone^related protein (PTHrP), tumor necrosis factor-a (TNF-a), receptor activator of nuclear factor-nB (RANK), RANK ligand (RANKL), and osteoprotegerin. Results: SCC VII cells rapidly multiplied in the masseter muscle of the mice. Bone invasion was evident only in the control group on micro-computed tomography. On TRAP-stained slices, the percentages of osteoclasts in groups 1 and 2 were significantly lower than that in the control group. The mRNA expressions of IL-6, PTHrP,THF-a, and RANK decreased as the concentration of YM529 increased. Conclusions: We conclude that various cancer-derived cytokines play important roles in the invasion of bone by OSCC. YM529, a third-generation bisphosphonate, can suppress osteoclastmediated bone invasion by OSCC. The mechanism of this effect might involve inhibition of cytokines such as IL-6, PTHrP,TNF-a, and RANK byYM529.

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Section: Discussionmentioning

confidence: 99%

Effect of YM529 on a Model of Mandibular Invasion by Oral Squamous Cell Carcinoma in Mice

Cui

Nomura²,

Noma³

et al. 2005

Clinical Cancer Research

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“…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%

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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“…Em acordo com nossos estudos estão os achados de Murakami et al que mostraram que o bisfosfato de tiludronato influencia a massa, estrutura e turnover do osso esponjoso (39)(40)(41) . Mosekilde et al chegaram a resultado semelhante, em relação ao risedronato e alendronato (8) .…”

Section: Discussionunclassified

O alendronato de sódio na prevenção da osteopenia secundária à imobilização gessada, em ratas: avaliação histomorfométrica

et al. 2008

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A possible mechanism of the specific action of bisphosphonates on osteoclasts: Tiludronate preferentially affects polarized osteoclasts having ruffled borders

Cited by 199 publications

References 29 publications

Effect of YM529 on a Model of Mandibular Invasion by Oral Squamous Cell Carcinoma in Mice

Effect of YM529 on a Model of Mandibular Invasion by Oral Squamous Cell Carcinoma in Mice

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

O alendronato de sódio na prevenção da osteopenia secundária à imobilização gessada, em ratas: avaliação histomorfométrica

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