Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo
Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo
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DOI：
10.1016/s8756-3282(98)00033-7
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发表时间：
1998-05-01
期刊：
影响因子：
4.1
通讯作者：
Girasole, G
中科院分区：
文献类型：
--
作者：
Giuliani, N;Pedrazzoni, M;Girasole, G
最近的体外研究结果表明，双膦酸盐，骨吸收的有效抑制剂，也可能对成骨细胞有直接的作用。本研究的目的是通过测量小鼠和人骨髓培养物中成纤维细胞集落形成单位（CFU-F）和成骨细胞集落形成单位（CFU-OB）的数量，寻找依替膦酸盐和阿仑膦酸盐对早期和晚期成骨细胞前体形成的潜在影响。在小鼠骨髓培养中，依替膦酸盐（10（-5）~ 10（-9）mol/L）可显著促进CFU-F的形成，以10（-5）mol/L作用最强（相对于对照值的平均增加+/- SD：106 +/- 17%;而阿仑膦酸钠具有双相效应，在浓度低于10（-7）mol/L时具有刺激性（78 +/- 5%; p < 0.001），在较高剂量时具有抑制性。在最高浓度（10（-5）mol/L和10（-6）mol/L）时，两种双膦酸盐也抑制CFU-OB的形成，但在较低浓度（依替膦酸盐10（-7）至10（-9）mol/L，阿仑膦酸盐10（-7）至10（-10）mol/L; p < 0.001）时，CFU-OB的形成受到显著刺激。在人骨髓培养中，阿仑膦酸钠（10（-8）至10（-12）mol/L）增加CFU-F形成，在10（-10）mol/L时效果最大（161 +/- 12%;p < 0.01）。仅在地塞米松（10（-8）mol/L）存在下观察到的CFU-OB形成在上述浓度下被阿仑膦酸钠显著刺激，在10（-10）mol/L时最大增加（133 +/- 34%; p < 0.001）。在骨髓培养物中，还研究了二膦酸盐对早期成骨细胞前体形成的体内短期影响，这些骨髓培养物来自每周皮下注射依替膦酸盐（0.3、3和30 mg/kg）或阿仑膦酸盐（0.3、3和30 μ g/kg）的年轻雌性小鼠，以及用两种最低剂量的两种药物治疗的老龄雌性小鼠。治疗1个月后，依替膦酸盐（0.3和3 mg/kg）和阿仑膦酸盐（0.3和3 μ g/kg）显着增加年轻和老年动物骨髓中CFU-F集落的数量，而最高剂量的两种药物对年轻小鼠没有影响。我们的研究结果，与以前报道的骨质疏松症的骨形成作用的观察结果，表明，双膦酸盐可能有，在体内，成骨细胞谱系的细胞的潜在相关的影响，从他们对破骨细胞的抑制作用不同。(C)1998年，Elsevier Science Inc. All rights reserved.
Recent in vitro findings suggest that bisphosphonates, potent inhibitors of osteoclastic bone resorption, may also have a direct action on osteoblasts. The purpose of this study was to search for potential effects of etidronate and alendronate on the formation of early and late osteoblastic cell precursors by measuring the number of colony-forming units for fibroblasts (CFU-F) and colony-forming units for osteoblasts (CFU-OB) in murine and human bone marrow cultures. In murine marrow cultures, etidronate (10(-5) to 10(-9) mol/L) significantly stimulated the formation of CFU-F with a maximal effect at 10(-5) mol/L (mean increase over control values +/- SD: 106 +/- 17%; p < 0.001), whereas alendronate had a biphasic effect, being stimulatory at concentrations below 10(-7) mol/L (78 +/- 5%; p < 0.001), and inhibitory at higher doses. The formation of CFU-OB was also inhibited hy both bisphosphonates at the highest concentrations (10(-5) mol/L and 10(-6) mol/L), but it was significantly stimulated at lower concentrations (from 10(-7) to 10(-9) mol/L for etidronate and 10(-7) to 10(-10) mol/L for alendronate; p < 0.001). In human bone marrow cultures, alendronate (10(-8) to 10(-12) mol/L) increased CFU-F formation with a maximal effect at 10(-10) mol/L (161 +/- 12%;p < 0.01). CFU-OB formation, observed only in the presence of dexamethasone (10(-8) mol/L), was markedly stimulated by alendronate at the above concentrations with a maximal increase at 10(-10) mol/L, (133 +/- 34%; p < 0.001). The in vivo short-term effects of bisphosphonates on the formation of early osteoblast precursors were also studied in bone marrow cultures from young female mice treated with weekly subcutaneous injections of etidronate (0.3, 3, and 30 mg/kg) or alendronate (0.3, 3, and 30 mu g/kg) and from aging female mice treated with the two lowest doses of both drugs. After 1 month of treatment, etidronate (0.3 and 3 mg/kg) and alendronate (0.3 and 3 mu g/kg) significantly increased the number of CFU-F colonies in the bone marrow from young and old animals, whereas the highest dose of both drugs had no effect in young mice. Our results, together with previously reported observations of bone-forming effects in osteoporosis, suggest that bisphosphonates may have, in vivo, a potentially relevant influence on cells of the osteoblastic lineage, distinct from their inhibitory action on osteoclasts. (C) 1998 by Elsevier Science Inc. All rights reserved.