Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis
Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis
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DOI：
10.1007/s00210-010-0596-4
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发表时间：
2011-03-01
影响因子：
3.6
通讯作者：
Okabe, Koji
中科院分区：
文献类型：
--
作者：
Kimachi, Keiichiro;Kajiya, Hiroshi;Okabe, Koji
已知双膦酸盐可直接抑制骨吸收并促进成熟破骨细胞凋亡。虽然双膦酸盐已被公认为治疗骨质疏松症和骨癌转移的最有效药物，但其对破骨细胞生成的确切作用和机制尚不清楚。本研究的目的是阐明含氮双膦酸盐是否影响破骨细胞的募集和分化。我们研究了唑来膦酸对两种破骨细胞前体RAW264.7细胞和骨髓细胞（BMC）中破骨细胞生成过程中NF-κ B受体激活因子（RANK）表达和细胞迁移的影响。在巨噬细胞集落刺激因子存在下，肿瘤坏死因子-α（TNF-α）和RANK配体（RANKL）以时间依赖性方式上调RAW264.7和BMC中的RANK表达。唑来膦酸（30和50 μ M）培养36小时后，破骨细胞前体的细胞活力没有影响。唑来膦酸（10和30 μ M）以剂量依赖性方式强烈抑制TNF-α和RANKL诱导的RANK上调。对RANK表达的抑制作用可能与NF-κ B通路的抑制有关，但与其他下游信号通路无关。唑来膦酸（30 μ M）还通过抑制甲羟戊酸途径抑制TNF-α和RANKL诱导的前体迁移。我们的研究结果表明，含氮双膦酸盐不仅抑制成熟的破骨细胞，但也阻止破骨细胞前体细胞分化和迁移到炎性骨质溶解病变。
Bisphosphonates have been known to directly inhibit bone resorption and promote apoptosis in mature osteoclasts. Although bisphosphonates have been recognized as the most effective drugs to treat osteoporosis and bone cancer metastasis, the exact effects and mechanism(s) of bisphosphonates on osteoclastogenesis are unclear. The aim of this study was to clarify whether nitrogen-containing bisphosphonates affect recruitment and differentiation in osteoclasts. We examined the effects of zoledronic acid on receptor activator of NF-kappa B (RANK) expression and cell migration during osteoclastogenesis in two types of osteoclast precursors, RAW264.7 cells and Bone marrow cells (BMCs). Tumor necrosis factor-alpha (TNF-alpha) and RANK ligand (RANKL) upregulated RANK expression in RAW264.7 and BMCs in the presence of macrophage colony stimulating factor in a time-dependent manner. Zoledronic acid (30 and 50 mu M) had no effect on cell viability in osteoclast precursors after 36 h of cultivation. Zoledronic acid (10 and 30 mu M) strongly inhibited TNF-alpha-and RANKL-induced upregulation of RANK in a dose-dependent manner. The inhibitory effects on RANK expression were likely to be associated with the suppression of the NF-kappa B pathway, but not other downstream signaling pathways. Zoledronic acid (30 mu M) also suppressed the TNF-alpha-and RANKL-induced migration of precursors by inhibiting the mevalonic acid pathway. Our results suggest that nitrogen-containing bisphosphonates not only inhibit mature osteoclasts but also prevent osteoclast precursors from differentiating and migrating towards inflammatory osteolysis lesions.