A study on mevalonic acid pathway-targeting therapy to recovery osteoclasts damaged with bisphosphonate

含氮双膦酸盐（BP）是治疗骨质疏松症和癌症骨转移等骨吸收性疾病的有效药物。众所周知，在拔牙后使用含氮双膦酸盐治疗的患者中，偶尔会发生颌骨骨坏死，称为BRONJ。虽然BRONJ很难治疗，并且长期困扰患者和牙医，但尚未建立任何有效的BRONJ治疗方法。BP的靶细胞为破骨细胞。BP通过抑制破骨细胞甲羟戊酸途径抑制破骨细胞骨吸收活性。为了恢复bp诱导的破骨细胞活性抑制，本研究研究了甲羟戊酸途径中间体香叶香醇（GGOH）对bp诱导的破骨细胞活性抑制的影响。因此，在体外培养的破骨细胞中添加GGOH可以恢复bp抑制的破骨细胞的多核、TRAP表达、细胞迁移能力和细胞融合促进因子STAMP的表达。本研究提示GGOH可中和BP对破骨细胞的不良影响。

Nitrogen-containing bisphosphonate (BP) is used as effective therapeutic agent for managing bone-resorbing diseases such as osteoporosis and cancer bone metastasis. It is well know n that osteonecrosis of the jaw occasionally occurs in the patients treated with nitrogen-containing bisphosphonate after tooth extraction, which is called as BRONJ. Although BRONJ is quite difficult to treat and annoys both the patients and dentists for a long time, any effective therapies for BRONJ have not been established. The target cell of BP is osteoclast. BP inhibits the mevalonic acid pathway of osteoclast to inhibit osteoclastic bone-resorbing activity. In order to recover the BP-induced inhibition of osteoclast activity, the effects of geranylgeraniol (GGOH), an intermediate of mevalonic acid pathway, on BP-induced inhibition of osteoclast activity was investigated in this study. As a result, the addition of GGOH to cultured osteoclasts restored multinucleation, TRAP expression, cell migratinability and the expression of cell fusion-promoting factor STAMP of BP-inhibited osteoclasts. This study suggests that GGOH may neutralize the adverse effects of BP in osteoclasts.