EFFECTS OF 2 NOVEL BISPHOSPHONATES ON BONE-CELLS IN-VITRO
EFFECTS OF 2 NOVEL BISPHOSPHONATES ON BONE-CELLS IN-VITRO
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DOI：
10.1016/s0169-6009(08)80055-4
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发表时间：
1994-08-01
期刊：
影响因子：
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通讯作者：
BRAIDMAN, IP
中科院分区：
文献类型：
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作者：
EVANS, CE;BRAIDMAN, IP
双膦酸盐现在被广泛用于治疗骨骼疾病，特别是在骨吸收不受控制的情况下，因为它们被认为是破骨的有效抑制剂。目前还不清楚双膦酸盐是通过抑制破骨细胞成熟还是通过阻断骨吸收机制发挥作用，对成骨细胞的影响也知之甚少。最近的研究表明，3-氨基-1，1-羟亚丙基-1，1-双膦酸治疗乳腺癌溶骨转移可能直接影响成骨细胞。我们研究了两种新型双膦酸类化合物CGP42446A和CGP42446A对胶原凝胶上培养的胎鼠颅骨破骨细胞生成的影响，以及作为手术患者骨外植体培养的人成骨细胞(HOB)破骨细胞的作用。我们还比较了这些新的双膦酸盐和apd的作用，后者在2.5×10(-6)M到2.5×10(-10)M的浓度下抑制破骨细胞的招募，即使这是在MCF7乳腺癌细胞的条件培养液刺激下也是如此。如果与妊娠19天的头盖骨一起培养，这种双膦酸盐尤其有效，因为此时存在更多未成熟的破骨细胞前体。如果使用妊娠20天的头盖骨，它含有更多的成熟细胞，它产生的抑制作用较小。相反，CGP 42446A(2.5×10~(-6)M~2.5×10~(-8)M)对胎龄20天的颅骨破骨细胞成熟的抑制作用强于19天。CGP47072有类似的作用模式，但不如其他两种化合物有效。在10(-5)M时，APD或CGP42446A显著抑制HOB数和DNA合成，但较低浓度时作用不明显。CGP47072不能抑制人成骨细胞的复制。这些作用不太可能是由于钙离子的螯合作用，因为这些化合物都不能模仿EDTA的结果，EDTA只在2.5×10(-6)M和10(-4)M的条件下才能有效地缩小人成骨细胞培养的破骨细胞尺寸。这些结果表明，三种双膦酸盐在低浓度时都能抑制破骨细胞的形成。APD可能影响较不成熟的破骨细胞前体细胞，CGP42446A和CGP47072可能影响较成熟的破骨细胞前体细胞在骨表面的融合。然而，在这些浓度下，对成骨细胞几乎没有影响。
Bisphosphonates are now widely used in the treatment of bone diseases, particularly where there is uncontrolled bone resorption, as they are known to be potent inhibitors of osteoclasis. It is still unclear whether the bisphosphonates act by inhibiting osteoclast maturation or by blocking the mechanism of bone resorption, and little is known of their effects on osteoblasts. Recent studies with 3-amino-1, hydroxypropylidene-1,1-bisphosphonic acid (APD) in the treatment of osteolytic metastases in breast cancer have suggested that APD may affect osteoblasts directly. We have now investigated the effects of two novel bisphosphonates, CGP 47072 and CGP 42446A on osteoclastogenesis in fetal rat calvariae cultured on collagen gels and on human osteoblasts (hOB) cultured as explants from bone taken from patients at surgery. We also compared the action of these new bisphosphonates with that of APD, which at concentrations of 2.5 x 10(-6) M to 2.5 x 10(-10) M inhibited osteoclast recruitment, even when this was stimulated by conditioned medium from MCF7 breast cancer cells. This bisphosphonate was particularly potent if cultured with calvaria taken at 19 days gestation, when more immature osteoclast precursors are present. If calvariae from 20 days gestation were used, which contain more mature cells, it produced less inhibition. In contrast, CGP 42446A (2.5 x 10(-6) M to 2.5 x 10(-8) M) was more effective in inhibiting osteoclast maturation in calvariae from 20 days gestation than in those from 19 days. CGP 47072 had a similar pattern of effects but was less potent than either of the other two compounds. APD or CGP 42446A at 10(-5) M significantly inhibited hOB numbers and DNA synthesis, but lower concentrations had little effect. CGP 47072 did not inhibit human osteoblast replication. It is unlikely that these effects are due to calcium chelation, as none of these compounds mimicked results obtained with EDTA, which was effective only at 2.5 x 10(-6) M in reducing osteoclast size and 10(-4) M in human osteoblast cultures. These results demonstrate that all three bisphosphonates are able to inhibit osteoclast formation at low concentrations. APD may be able to influence less mature osteoclast precursors and CGP 42446A and CGP47072 may exert their effects on the fusion of more mature precursor cells on the bone surface. At these concentrations, however, there is little or no effect on osteoblasts.