Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778.
Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778.
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发表时间：
1999-09
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通讯作者：
K. Notoya;H. Nagai;T. Oda;M. Gotoh;T. Hoshino;H. Muranishi;S. Taketomi;T. Sohda;H. Makino
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作者：
K. Notoya;H. Nagai;T. Oda;M. Gotoh;T. Hoshino;H. Muranishi;S. Taketomi;T. Sohda;H. Makino
TAK-778 [(2R,4S)-(-)-N-(4-二乙氧基磷酰基甲基苯基)-1,2,4,5-四氢-4-甲基-7,8-亚甲二氧基-5-氧代-3-苯并硫杂庚英-2-甲酰胺； mw 505.53]，一种新型成骨细胞分化促进化合物，在体外和体内模型中进行了表征。在地塞米松存在的情况下，在大鼠骨髓基质细胞培养物中，10(-6) M 及更高剂量的 TAK-778 可有效促进骨样结节的形成。这伴随着细胞碱性磷酸酶活性、可溶性胶原蛋白释放和骨钙素分泌的增加。在培养条件下，TAK-778还刺激转化生长因子-β和胰岛素样生长因子-I的分泌，表明TAK-778可能通过自分泌/旁分泌机制对成骨细胞分化发挥调节作用。此外，使用由可生物降解聚合物聚（dl-乳酸/乙醇酸）（PLGA）组成的缓释微胶囊，在骨缺损和截骨动物模型中研究了 TAK-778 的体内成骨潜力。对大鼠颅骨缺损单次局部注射 TAK-778/PLGA 微胶囊 (PLGA-MC)（0.2-5 mg/位点），4 周后导致缺损内新骨面积呈剂量依赖性增加。当将含有 TAK-778/PLGA-MC（4 毫克/颗粒）的颗粒填充到位以填充兔子的胫骨节段缺损时，该颗粒在 2 个月内诱导骨愈合，而安慰剂颗粒则没有。此外，在兔胫骨截骨部位单次局部应用 TAK-778/PLGA-MC（10 毫克/位点）可增强愈伤组织形成，并伴随 30 天后断裂力的增加。这些结果首次表明，非内源性化合物可以在体外有效促进成骨，并在体内骨骼再生和骨修复过程中增强新骨形成，并且应该有助于刺激骨折愈合。
TAK-778 [(2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4, 5-tetrahydro-4-methyl-7, 8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxyamide; mw 505.53], a novel osteoblast differentiation promoting compound, was characterized in vitro and in vivo models. TAK-778 at doses of 10(-6) M and higher promoted potently bone-like nodule formation in the presence of dexamethasone in rat bone marrow stromal cell culture. This was accompanied by increases in cellular alkaline phosphatase activity, soluble collagen release, and osteocalcin secretion. Under the culture conditions, TAK-778 also stimulated the secretion of transforming growth factor-beta and insulin-like growth factor-I, indicating that TAK-778 may exert regulatory effects on osteoblast differentiation via autocrine/paracrine mechanisms. Furthermore, the in vivo osteogenic potential of TAK-778 was studied in bony defect and osteotomy animal models, using sustained release microcapsules consisted of a biodegradable polymer, poly (dl-lactic/glycolic) acid (PLGA). Single local injection of TAK-778/PLGA-microcapsules (PLGA-MC) (0.2-5 mg/site) to rat skull defects resulted in a dose-dependent increase in new bone area within the defects after 4 weeks. When the pellet containing TAK-778/PLGA-MC (4 mg/pellet) was packed into place to fill the tibial segmental defect in rabbit, this pellet induced osseous union within 2 months, whereas the placebo pellet did not. In addition, single local application of TAK-778/PLGA-MC (10 mg/site) to rabbit tibial osteotomy site enhanced callus formation accompanied by an increase in breaking force after 30 days. These results reveal for the first time that a nonendogenous chemical compound promotes potently osteogenesis in vitro and enhances new bone formation during skeletal regeneration and bone repair in vivo and should be useful for the stimulation of fracture healing.