van beek E, Löwik C, van der Pluijm G, Papapoulos S
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
J Bone Miner Res. 1999 May;14(5):722-9. doi: 10.1359/jbmr.1999.14.5.722.
Bisphosphonates, synthetic compounds used in the treatment of skeletal disorders, suppress osteoclast-mediated bone resorption by a yet unidentified mechanism. Previous studies showed that some bisphosphonates can inhibit enzymes of the mevalonate pathway, and nitrogen-containing bisphosphonates inhibit protein prenylation in mouse macrophages. In the present study, we examined the involvement of the mevalonate pathway in basal and bisphosphonate-inhibited osteoclastic resorption in fetal mouse long bone explants, an experimental model representative of the in vivo action of bisphosphonates. Mevastatin inhibited bone resorption at concentrations similar to those of the potent bisphosphonate ibandronate. This effect could be totally reversed by the addition of mevalnate and geranylgeraniol but not farnesol. The first two intermediates but not the latter could also stimulate basal bone resorption. The inhibitory effect of ibandronate on bone resorption could be totally reversed by the addition of geranylgeraniol and to a small extent only by mevalonate and farnesol, indicating that the bisphosphonate acts at a level of the mevalonate pathway different from that of mevastatin. Histologic sections of ibandronate-treated bone explants showed further rescue of functioning osteoclasts during concomitant treatment with geranylgeraniol. Finally, the reversibility of bisphosphonate inhibited osteoclastic resorption by geranylgeraniol was also demonstrated for the potent nitrogen-containing bisphosphonates alendronate, olpadronate, and risedronate but not for the non-nitrogen-containing bisphosphonates clodronate and etidronate. These studies demonstrate that protein geranylgeranylation but not farnesylation is important for osteoclast-mediated bone resorption and that nitrogen-containing bisphosphonates exert their antiresorptive action probably by affecting enzymes of the mevalonate pathway involved in the generation of geranylgeranyl pyrophosphate.
双膦酸盐是用于治疗骨骼疾病的合成化合物，其通过一种尚未明确的机制抑制破骨细胞介导的骨吸收。先前的研究表明，一些双膦酸盐可以抑制甲羟戊酸途径的酶，含氮双膦酸盐可抑制小鼠巨噬细胞中的蛋白质异戊二烯化。在本研究中，我们在胎鼠长骨外植体中研究了甲羟戊酸途径在基础和双膦酸盐抑制的破骨细胞吸收中的作用，该实验模型代表了双膦酸盐的体内作用。美伐他汀在与强效双膦酸盐伊班膦酸钠相似的浓度下抑制骨吸收。添加甲羟戊酸和香叶基香叶醇可完全逆转这种作用，但添加法尼基醇则不能。前两种中间体而非后者也可刺激基础骨吸收。添加香叶基香叶醇可完全逆转伊班膦酸钠对骨吸收的抑制作用，添加甲羟戊酸和法尼基醇只能部分逆转，这表明双膦酸盐作用于甲羟戊酸途径的水平与美伐他汀不同。伊班膦酸钠处理的骨外植体的组织学切片显示，在与香叶基香叶醇同时处理期间，功能性破骨细胞得到进一步挽救。最后，对于含氮强效双膦酸盐阿仑膦酸钠、奥帕膦酸钠和利塞膦酸钠，香叶基香叶醇也证明了双膦酸盐抑制的破骨细胞吸收的可逆性，但对于不含氮的双膦酸盐氯膦酸盐和依替膦酸盐则不然。这些研究表明，蛋白质香叶基香叶基化而非法尼基化对于破骨细胞介导的骨吸收很重要，含氮双膦酸盐可能通过影响参与香叶基香叶基焦磷酸生成的甲羟戊酸途径的酶来发挥其抗吸收作用。
