Sustained‐release microcapsules of a bone formation stimulant, TAK‐778, for local injection into a fracture site

Hoshino, T.; Saito, Kazuhiro; Muranishi, Hiroya; Sohda, Takashi; Ogawa, Yutaka

doi:10.1002/jps.1163

Cited by 9 publications

(4 citation statements)

References 20 publications

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“…TAK-778 has been shown to induce bone regeneration and stimulate fracture healing in animal models [Hoshino et al, 2000[Hoshino et al, , 2001. In vitro studies have shown that TAK-778 increases alkaline phosphatase (ALP) activity, one of the markers characteristic of the osteoblast phenotype, in rat bone marrow cell culture, and enhances the action of BMP in mouse osteoblastic cell line MC3T3-E1 .…”

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TAK‐778 enhances osteoblast differentiation of human bone marrow cells

Rosa

Beloti

2003

J of Cellular Biochemistry

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TAK-778 has been shown to induce bone growth in in vitro and in vivo models. However, there are no studies evaluating the effect of TAK-778 on human cells. Thus, the aim of this study was to investigate osteogenesis induced by TAK-778 on human bone marrow cells. Cells were cultured in 24-well culture plates at a cell density of 2 x 10(4) cells/well in culture medium containing TAK-778 (10(-7), 10(-6), and 10(-5) M, each) or vehicle. During the culture period, cells were incubated at 37 degrees C in a humidified atmosphere of 5% CO(2) and 95% air. For attachment evaluation, cells were cultured for 4 and 24 h. After 7, 14, and 21 days, cell proliferation, cell viability, total protein content, alkaline phosphatase (ALP) activity, and bone-like formation were evaluated. Data were compared by ANOVA and Duncan's multiple range test. TAK-778 did not affect cell attachment and viability. Cell number was reduced by TAK-778 in all time period evaluated in a dose-dependent way. The effect of TAK-778 on total protein content, ALP activity and bone-like formation was a dose-dependent increase. The present results suggest that initial cell events such as cell attachment are not affected by TAK-778 while events that indicate osteoblast differentiation including reduced cell proliferation, and increased both ALP activity and bone-like formation are enhanced by TAK-778 in a time and dose-dependent way. It means that TAK-778 could be a useful drug to enhance new bone formation in clinical situations that require rapid restoration of physiologic function, such as orthopedic and maxillofacial surgery.

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confidence: 99%

TAK‐778 enhances osteoblast differentiation of human bone marrow cells

Rosa

Beloti

2003

J of Cellular Biochemistry

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“…TAK‐778 has been shown to induce bone regeneration and stimulate fracture healing in animal models [Hoshino et al, 2000, 2001]. In vitro studies have shown that TAK‐778 increases both alkaline phosphatase (ALP) activity, one of the markers characteristic of the osteoblast phenotype, in rat bone marrow cell culture, and enhances the action of bone morphogenetic proteins in mouse osteoblastic cell line MC3T3‐E1 [Oda et al, 1999].…”

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TAK‐778 enhances osteoblast differentiation of human bone marrow cells via an estrogen‐receptor‐dependent pathway

Rosa

Beloti

2004

J of Cellular Biochemistry

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TAK-778, a derivative of ipriflavone, has been shown to induce bone growth in in vitro and in vivo models. However, there are no studies evaluating by which mechanism TAK-778 exerts its effect. Considering the evidences that its precursors act via classical estrogen-receptor (ER)-mediated signaling, in the present study, we tested the hypothesis that TAK-778 induces osteogenesis in human bone marrow cell culture via an ER-dependent pathway. Cells were cultured in 24-well culture plates at a cell density of 2 x 10(4) cells/well in culture medium containing: TAK-778 (10(-5) M), Tamoxifen (10(-5) M), TAK-778 (10(-5) M) + Tamoxifen (10(-5) M), and vehicle. During the culture period, cells were incubated at 37 degrees C in a humidified atmosphere of 5% CO(2) and 95% air. At 7, 14, and 21 days, cell proliferation, cell viability, total protein content, alkaline phosphatase (ALP) activity, and bone-like formation were evaluated. Data were compared by two-way ANOVA and Duncan's multiple range test. TAK-778 did not affect cell viability. Cell number was reduced by TAK-778. Total protein content, ALP activity, and bone-like formation were increased by TAK-778. In general, Tamoxifen did not have any effect on cell behavior. However, when cells were cultured in medium containing both TAK-778 and Tamoxifen, the effect of TAK-778 on osteoblast differentiation was inhibited. The present results show that TAK-778 enhances osteoblast differentiation in human bone marrow cell culture, at least in part, via an ER-dependent pathway, since its effect was inhibited by Tamoxifen, a well-known estrogen receptor antagonist.

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“…7,8 In addition, other investigators observed that TAK-778 enhances bone fracture healing and bone formation on both hydroxyapatite and glass ceramics. 6,9,11,12 However, no effects of TAK-778 on osseointegration of titanium implants were observed, despite the use of a sustained-release system similar to that used in the in vivo studies previously performed.…”

Section: Discussionmentioning

confidence: 97%

“…4 6 Recently, we showed that TAK-778 enhances osteoblast differentiation in human bone marrow cell culture in a dose-dependent way. 7 Also, it was observed that TAK-778 maintains its effect on osteoblast differentiation in the presence of titanium. 8 To evaluate the in vivo osteogenic potential of TAK-778, it was developed a sustained release microcapsules consisted of a biodegradable polymer, poly (dl-lactic/glycolic) acid, and TAK-778, which allow the drug release for 4 weeks after the injection.…”

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confidence: 97%