Histopathological study on bone changes induced by recombinant granulocyte colony-stimulating factor in rats

Suzuki, Masami; Sakamaki, Yoshiyuki; Miyoshi, Akio; Adachi, Kenji; Usami, Masayoshi; Nakayama, Hiroyuki; Doi, Kunio

doi:10.1016/s0940-2993(97)80024-3

Cited by 12 publications

(9 citation statements)

References 21 publications

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“…Very few data are available on the potential interactions between bisphosphonates and growth factors, but it was recently reported that administration of bisphosphonates to patients with bone metastases significantly decreases serum FGF-2 concentrations (Zimering, 2002). It has also been shown that pamidronate inhibits the effects of GH and decreases IGF-I levels in rats (Kapitola et al, 2000), or inhibits the effects of G-CSF on bone cells (Suzuki et al, 1999). Our first experiments showed that when both growth factors and bisphosphonates were simultaneously added to cell cultures, the stimulatory effects of growth factors on cell survival were markedly decreased (for IGFs) or even abolished (for FGF-2).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

2003

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“…Conversely, the serum concentration in G-CSF transgenic mice is significantly higher than that of their littermate controls . In rats treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF), accelerated osteogenesis, resulting from intramembranous ossification and bone resorption, was observed in the metaphyseal spongiosa (Suzuki et al, 1999).…”

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confidence: 99%

Overexpression of the Granulocyte Colony-Stimulating Factor Gene Impairs Bone Morphogenetic Protein Responsiveness in Mice

Kuwabara

Wada

Oda

et al. 2001

Laboratory Investigation

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SUMMARY:Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic growth factor regulating the production and differentiation of neutrophils. We previously demonstrated that permanent overexpression of G-CSF in transgenic mice produces a dramatic enlargement of the bone cavity and reduction of bone mass. This phenotype was shown to be associated with an increase of osteoclast-mediated bone resorption. As a way of determining the role of G-CSF in bone formation in vivo, an ectopic bone was induced subcutaneously into G-CSF transgenic mice by bone morphogenetic protein (BMP)-2, a potent initiator of bone and cartilage from undifferentiated mesenchymal cells. A BMP-2/atelocollagen pellet containing recombinant human BMP-2 was implanted into a dorsal subfascial pocket. At one week after implantation, proliferation of mesenchymal cells around the implant was significantly decreased in transgenic mice compared with control mice. At three weeks, an ectopic bone containing bone marrow was formed both in transgenic and control mice. However, the ectopic bones of the transgenic mice were smaller and less consistent than those of control mice, and the calcium contents were reduced to 56.2% of those of controls. The ectopic bone in the G-CSF mice showed poor development of both lamellar and trabecular bone. Semiquantitative reverse transcription-polymerase chain reaction analysis of the ectopic bone at 3 weeks disclosed no significant differences in the mRNA levels of type I collagen, osteopontin, and osteocalcin between G-CSF mice and control mice. Immunohistochemical study in G-CSF mice showed reduced staining of osteocalcin in the bone matrix surrounding the reduced number of osteoblasts. The half-life of BMP in the implants was prolonged to 7 to 9 days in the G-CSF mice, whereas it was 5 days in the control mice. Collectively, the permanent expression of G-CSF may retard the differentiation process of osteoblasts by impairing the initial induction of mesenchymal cells, resulting in reduction of bone mass, suggesting that G-CSF regulates the bone metabolism by modulating both osteoclast and osteoblast function. Furthermore, it is suggested that G-CSF is a potent modulator of the BMP-2

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“…It has been established that osteoclasts, the principal cells responsible for bone resorption, are derived from hematopoietic stem cells (20) and that the CSFs, especially macrophage CSF, regulate the proliferation and differentiation of osteoclast progenitors (2,6,8,11,13,14,17,19,22,24). Keller and Smalling (7) and Suzuki et al (21) have recently demonstrated that bone changes characterized by accelerated osteoclastic bone resorption and osteogenesis are observed in growing rats exogenously administered high doses of recombinant human G-CSF (rhG-CSF) for a long period. We observed that those changes are frequently found at the site of physiologically active bone resorption in the growth phase, that is, the trabeculae of metaphyseal spongy bone and the endosteum region of diaphyseal compact bone (21).…”

Section: Introductionmentioning

confidence: 99%

“…Keller and Smalling (7) and Suzuki et al (21) have recently demonstrated that bone changes characterized by accelerated osteoclastic bone resorption and osteogenesis are observed in growing rats exogenously administered high doses of recombinant human G-CSF (rhG-CSF) for a long period. We observed that those changes are frequently found at the site of physiologically active bone resorption in the growth phase, that is, the trabeculae of metaphyseal spongy bone and the endosteum region of diaphyseal compact bone (21). This finding suggests that the development of bone changes induced by rhG-CSF may be related to age-dependent bone conditions including the bone growth.…”

Section: Introductionmentioning

confidence: 99%

The Age-Related Difference in Bone Changes in Rats Induced by Recombinant Human Granulocyte Colony-Stimulating Factor

Suzuki¹,

Sakamaki²,

Miyoshi³

et al. 1997

Toxicol Pathol

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We examined the bone changes in recombinant human granulocyte colony-stimulating factor (rhG-CSF)-treated young and young adult rats in order to investigate the effect of age-related conditions of bone growth on the bone changes induced by rhG-CSF. Recombinant human G-CSF (100 and 1,000 μg/kg/day) was given to rats by daily intravenous injection for 28 days starting at the age of either 6 or 14 wk, and the hindlimb bones were evaluated histopathologically. In the young rats, bone lesions were observed in the 100-and 1,000-μg/kg groups. In the young adult rats, lesions were found only in the 1,000-μg/kg group. The lesions involved accelerated osteoclastic bone resorption and osteogenesis due to intramembranous ossification, and there was no age-related difference in these histopathological findings. However, both the incidence of bone involvement and the severity of lesions were greater in the young rats than in the dose-matched young adult rats. The results suggest that the higher dose of rhG-CSF may intrinsically induce bone lesions of a particular histopathological nature in rats regardless of their age, and the action of rhG-CSF on bone may be stronger in young growing rats than in young adults.

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Histopathological study on bone changes induced by recombinant granulocyte colony-stimulating factor in rats

Cited by 12 publications

References 21 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

Overexpression of the Granulocyte Colony-Stimulating Factor Gene Impairs Bone Morphogenetic Protein Responsiveness in Mice

The Age-Related Difference in Bone Changes in Rats Induced by Recombinant Human Granulocyte Colony-Stimulating Factor

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