Bisphosphonate‐enoxacin inhibit osteoclast formation and function by abrogating RANKL‐induced JNK signalling pathways during osteoporosis treatment

破骨细胞 骨质疏松症 骨吸收 去卵巢大鼠 兰克尔 双膦酸盐 化学 药理学 内分泌学 癌症研究 医学 受体 内科学 雌激素 激活剂(遗传学)
作者
Qiang Xu,Ping Zhan,Xiaofeng Li,Fengbo Mo,Huaen Xu,Yuan Liu,Qi Lai,Bin Zhang,Min Dai,Xuqiang Liu
出处
期刊:Journal of Cellular and Molecular Medicine [Wiley]
卷期号:25 (21): 10126-10139 被引量:14
标识
DOI:10.1111/jcmm.16949
摘要

Osteoporosis is an age-related disease characterized by low mineral density, compromised bone strength and increased risk of fragility fracture. Most agents for treating osteoporosis focus primarily on anti-resorption by inhibiting osteoclast activity. Bisphosphonate (BP) is a potent anti-resorptive agent that has been used clinically for decades and is proven to be effective. However, BP has a variety of side effects and is far from being an ideal anti-osteoporosis agent. BP selectively binds to calcium crystals, which are subsequently taken up or released by osteoclasts. Based on the action of BP, we previously demonstrated the inhibitory effect of a novel bone-targeting BP derivative, bisphosphonate-enoxacin (BE). In the current study, we used bone marrow-derived osteoclast cultures to further assess the inhibitory effect of BE on osteoclastogenesis and employed reverse transcription PCR and real-time PCR to examine expression of osteoclast-specific genes. Additionally, we used bone resorption and F-actin immunofluorescence assays to evaluate the effect of BE on osteoclast function and investigated the potential mechanisms affecting osteoclast differentiation and function in vitro. Furthermore, an ovariectomized (OVX) rat model was established to evaluate the therapeutic effects of BE on preventing bone loss. Results showed that BE exerted potent inhibitory effects on osteoclast formation and bone resorption by specifically abrogating RANKL-induced JNK signalling, and that it preserved OVX rat bone mass in vivo without any notable side effects. Collectively, these results indicated that the BP derivative BE may have significant potential as a treatment for osteoporosis and other osteolytic diseases.
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