破骨细胞
兰克尔
化学
下调和上调
蛋白激酶B
连接器
激活剂(遗传学)
癌症研究
骨吸收
细胞凋亡
药理学
受体
生物化学
内科学
生物
医学
操作系统
基因
计算机科学
作者
Ying Peng,Qingzhu Liu,Dong Xu,Ké Li,Hang Li,Ling Qiu,Jianguo Lin
摘要
Abstract Bisphosphonates (BPs), especially zoledronic acid (ZOL), are clinically used to treat osteolytic bone lesions. However, serious side‐effects may be also induced during the therapeutic process. To improve the BPs drugs, here, we investigated the effects of a series of ZOL derivatives with increasing number of methylene linker between the imidazole ring and the P–C–P backbone named IPrDP, IBDP, IPeDP, and IHDP on cell viability and receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast differentiation, function and apoptosis induction in mouse bone marrow‐derived macrophages (BMMs). Our results suggested that IPeDP and IHDP, which contains 4 and 5 methylene linkers, respectively, exerted lower toxicity on BMMs compared with ZOL, IPrDP, and IBDP, which contains 1, 2, and 3 methylene linkers respectively. At concentrations below cytotoxicity threshold, IPeDP and IHDP possessed strong abilities of antiosteoclast formation, antibone absorption, and inducing osteoclast apoptosis, which were similar to ZOL and more powerful than IPrDP and IBDP. The mechanism behind these effects of IPeDP and IHDP might involve the interference of small GTPases prenylation through suppression of mevalonate pathway. The downregulation of JNK and Akt phosphorylation and subsequent inhibition of the expression of c‐Fos and NFATc1 might also be involved. Our results supported the potential usage of IPeDP and IHDP to treat bone‐related disorders involving increased osteoclastogenesis. Our attempt to extend the methylene linker between the imidazole ring and the P–C–P backbone of ZOL also reveals some regularities between the structure and properties of the BPs drugs.
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