Alakangas A, Selander K, Mulari M, Halleen J, Lehenkari P, Mönkkönen J, Salo J, Väänänen Kalervo
Institute of Biomedicine, Department of Anatomy, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.
Calcif Tissue Int. 2002 Jan;70(1):40-7. doi: 10.1007/s002230010047. Epub 2001 Dec 21.
The nitrogen-containing bisphosphonate alendronate inhibits osteoclast-mediated bone resorption through inhibition of the mevalonate pathway. This results in impaired protein prenylation and may affect the function of small GTPases in osteoclasts. Since these proteins are important regulators of vesicle transport in cells, we investigated the possible interference of alendronate with these processes in isolated rat osteoclasts. We show here that alendronate-induced inhibition of bone resorption coincides with accumulation of tartrate-resistant acid phosphatase- and electron dense material-containing tubular vesicles in osteoclasts. Alendronate-induced changes in osteoclasts also included widening of the sealing zone areas and incomplete organization of tight attachments and ruffled borders. Osteoclasts also appeared partially detached from the bone surface, and organic matrix was typically dissolved only at the edges of the resorption pits on alendronate-coated bone slices. In contrast, resorption pits on the control and clodronate-coated bone slices were thoroughly resorbed. Inhibition of bone resorption by alendronate was not, however, related to a decrease in osteoclast number. In conclusion, our findings suggest that alendronate inactivates osteoclasts by mechanisms that impair their intracellular vesicle transport, apoptosis being only a secondary phenomenon to this.
含氮双膦酸盐阿仑膦酸钠通过抑制甲羟戊酸途径来抑制破骨细胞介导的骨吸收。这会导致蛋白质异戊二烯化受损，并可能影响破骨细胞中小GTP酶的功能。由于这些蛋白质是细胞中囊泡运输的重要调节因子，我们研究了阿仑膦酸钠对分离的大鼠破骨细胞中这些过程的可能干扰。我们在此表明，阿仑膦酸钠诱导的骨吸收抑制与破骨细胞中抗酒石酸酸性磷酸酶和含电子致密物质的管状囊泡的积累相一致。阿仑膦酸钠诱导的破骨细胞变化还包括封闭区面积增宽以及紧密连接和褶皱缘的组织不完整。破骨细胞也似乎部分从骨表面脱离，并且在阿仑膦酸钠包被的骨切片上，有机基质通常仅在吸收陷窝的边缘溶解。相比之下，对照和氯膦酸盐包被的骨切片上的吸收陷窝被彻底吸收。然而，阿仑膦酸钠对骨吸收的抑制与破骨细胞数量的减少无关。总之，我们的研究结果表明，阿仑膦酸钠通过损害其细胞内囊泡运输的机制使破骨细胞失活，凋亡只是由此产生的次要现象。
