Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: Role of the akt pathway and the ERK/Bim axis
Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: Role of the akt pathway and the ERK/Bim axis
复制标题
DOI：
10.1002/art.30646
复制
发表时间：
2011-12-01
影响因子：
--
通讯作者：
Tanaka, Sakae
中科院分区：
文献类型：
--
作者：
Matsumoto, Takumi;Nagase, Yuichi;Tanaka, Sakae
目的含氮双膦酸盐是治疗骨质疏松症最成功的药物之一。本研究的目的是阐明一种典型的含氮双膦酸盐利塞膦酸酯的作用机理。以小鼠骨髓巨噬细胞为材料，体外培养破骨细胞，观察利塞膦酸盐对破骨细胞凋亡和骨吸收活性的影响。通过AKT-1和MEK-1的基因诱导和Bim基因的缺失来研究利塞膦酸的作用机制。对破骨细胞抗凋亡的BIM(-/-)小鼠进行利塞膦酸治疗，并对其进行放射学、生化和组织学分析。利塞膦酸通过线粒体依赖途径诱导破骨细胞凋亡，并增加Bim的表达，Bim缺失和结构性激活的MEK-1的引入抑制了利塞膦酸的促凋亡作用。相反，利塞膦酸诱导的骨吸收抑制可通过诱导结构性活性Akt-1而完全逆转，但不能通过Bim缺失或结构性活性MEK-1的引入而逆转。这些结果表明，破骨细胞的凋亡和骨吸收活性分别通过ERK/Bim轴和Akt途径进行调节，利塞膦酸对这两种途径均有抑制作用。尽管利塞磷酸钠抑制了Bim(-/-)小鼠破骨细胞的凋亡，但利塞膦酸治疗增加了Bim(-/-)小鼠的骨密度，与野生型小鼠的水平相当。我们的研究结果表明，利塞膦酸盐在体内的抗吸收作用主要是通过抑制破骨细胞的骨吸收活性而不是通过诱导破骨细胞的凋亡来实现的。
Objective Nitrogen-containing bisphosphonates are one of the most successful therapeutics for osteoporosis. The aim of this study was to elucidate the functional mechanism of one of the typical nitrogen-containing bisphosphonates, risedronate.Methods. Osteoclasts generated from murine bone marrow macrophages were treated with risedronate in vitro, and its effects on apoptosis and boneresorbing activity were examined. The mechanism of action of risedronate was examined by gene induction of constitutively active Akt-1 and constitutively active MEK-1, and by gene deletion of Bim. Bim(-/-) mice, in which osteoclasts were resistant to apoptosis, were treated with risedronate and analyzed radiographically, biochemically, and histologically.Results. Risedronate induced osteoclast apoptosis through the mitochondria-dependent pathway with an increased expression of Bim, and the proapoptotic effect of risedronate was suppressed by Bim deletion and constitutively active MEK-1 introduction. In contrast, the risedronate-induced suppression of bone resorption was completely reversed by inducing constitutively active Akt-1, but not by Bim deletion or constitutively active MEK-1 introduction. These results suggested that apoptosis and bone-resorbing activity of osteoclasts were regulated through the ERK/Bim axis and the Akt pathway, respectively, both of which were suppressed by risedronate. Although osteoclast apoptosis in response to risedronate administration was suppressed in the Bim(-/-) mice, risedronate treatment increased bone mineral density in Bim(-/-) mice at a level equivalent to that in wild-type mice.Conclusion. Our findings indicate that the antiresorptive effect of risedronate in vivo is mainly mediated by the suppression of the bone-resorbing activity of osteoclasts and not by the induction of osteoclast apoptosis.