EFFECTS OF BISPHOSPHONATES APD AND HEBP ON BONE METABOLISM IN-VITRO
EFFECTS OF BISPHOSPHONATES APD AND HEBP ON BONE METABOLISM IN-VITRO
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DOI：
10.1016/8756-3282(95)00044-e
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发表时间：
1995-04-01
期刊：
影响因子：
4.1
通讯作者：
TENENBAUM, HC
中科院分区：
文献类型：
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作者：
GOZIOTIS, A;SUKHU, B;TENENBAUM, HC
虽然双膦酸盐对骨吸收的影响已被充分证明，但它们对骨形成的影响并不清楚，因此，本研究进行了体外研究，以阐明双膦酸盐在骨形成调节中所起的作用。为了评价双膦酸盐介导的体外骨形成调节，两种药物，乙烷-1-羟基，1-二磷酸，（依替膦酸盐）（HEBP）和第二代双膦酸盐，1-羟基-1-氨基亚丙基-1，1-磷酸二钠在鸡骨膜成骨（CPO）模型中评估了帕米膦酸盐（APD），在这项研究中，通过定量荧光组织化学方法在细胞水平上评估了药物诱导的碱性磷酸酶的变化，通过放射自显影（[H-3]胸苷）定量细胞增殖。矿化和基质的生产进行了测量形态，而胶原蛋白的合成和降解进行了生化测定。这些数据表明，除了它们对骨吸收的影响外，双膦酸盐对骨形成和其他成骨参数具有显著和直接的影响，HEBP可能影响细胞增殖（75-80%减少，p < 0.05）在远离骨的区域;成骨细胞层碱性磷酸酶阳性细胞数增多（相对于对照组的两倍，p < 0.05）在12天的培养物中，HEBP而不是APD在培养的早期阶段阻止矿化诱导的基质合成抑制。在用β-甘油磷酸盐诱导矿化的6天培养物中，（GP）与HEBP共处理诱导胶原合成增加70%。此外，CPO培养物中胶原的降解被HEBP抑制（25%），在较小程度上被APD抑制（8%），虽然在用双膦酸盐或GP的各种方案处理的12天培养物中测量的骨-类骨质面积没有差异，与仅用GP相比，在用GP和HEBP处理的6天培养物中检测到骨-类骨质面积的明显增加。这可能表明，最初，当矿化被抑制时，成骨细胞可能被诱导合成增加体积的骨基质总之，这些发现表明，尽管双膦酸盐确实对骨吸收具有充分记载的作用，但它们对骨形成的作用也可能是重要的。数据进一步表明，这些药物可能影响体外骨生成，部分是通过它们对成骨细胞中的矿化和可能的分化或表型表达的影响。
Although the effects of the bisphosphonates on resorption have been well documented, their effects on bone formation are not as clear, Therefore, this investigation was undertaken to elucidate the role played by bisphosphonates in the regulation of bone formation in vitro, To evaluate bisphosphonate-mediated regulation of bone formation in vitro, the effects of two drugs, ethane-1-hydroxy,1-diphosphate (Etidronate) (HEBP), and the second-generation bisphosphonate, disodium-1-hydroxy-1-aminopropylidine-1, phate (Pamidronate) (APD), were assessed in the chick periosteal osteogenesis (CPO) model, In this study, drug-induced changes in alkaline phosphatase were assessed at the cellular level by means of quantitative fluorescence histochemistry, Cellular proliferation was quantified by means of autoradiography ([H-3]thymidine). Mineralization and matrix production were measured morphometrically, whereas collagen synthesis and degradation were measured biochemically. The data suggest that in addition to their effects on bone resorption, the bisphosphonates have marked and direct effects on bone formation and other parameters of osteogenesis, HEBP may affect cellular proliferation (75-80% reduction, p < 0.05) in zones distant from bone; alkaline phosphatase positive cell numbers were increased in the osteoblastic layer of cells (twofold relative to control, p < 0.05) in 12-day cultures, HEBP, but not APD, prevented mineralization-induced suppression of matrix synthesis in early stages of culture, In 6-day cultures induced to mineralize with beta-glycerophosphate, (GP) cotreatment with HEBP induced a 70% increase in collagen synthesis, In addition, degradation of collagen in the CPO cultures was inhibited by HEBP (25%) and to a lesser extent by APD (8%), Although there were no differences in bone-osteoid areas measured in 12-day cultures treated with various regimens of bisphosphonate or GP, a clear increase in bone-osteoid area was detected in 6-day cultures treated with GP and HEBP as compared to GP only, This may suggest that initially, osteoblasts may be induced to synthesize increased volumes of bone matrix when mineralization is inhibited (e,g,, with HEBP), but that over time the osteoblasts make the same amount of matrix, Taken together, these findings indicate that whereas the bisphosphonates do have well-documented effects on bone resorption, their effects on bone formation may also be important, The data suggest further that these drugs may affect osteogenesis in vitro, in part through their effects on mineralization and perhaps on differentiation or phenotypic expression in osteoblasts.