RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia
RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia
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DOI：
10.1016/j.bone.2021.116301
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发表时间：
2022-03-01
期刊：
影响因子：
4.1
通讯作者：
Zhao, Xuefeng
中科院分区：
文献类型：
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作者：
Liu, Zhongyu;Yin, Yijia;Zhao, Xuefeng
纤维性发育不良 (FD) 是一种罕见的骨病，由骨骼干细胞中的 GNAS 突变引起，通常起源于儿童期并在儿童期恶化。迄今为止，尽管 FD 的病因已得到充分认识，但尚无治愈方法。研究表明，破骨细胞生成过度活跃是由 RANKL 表达升高引起的，这使得 RANKL 抑制成为一种潜在的治疗方法。尽管人类单克隆抗 RANKL 抗体狄诺塞麦已用于 FD 患者，但 RANKL 抑制对 FD 治疗的作用和机制仍需评估。狄诺塞麦价格昂贵且只能注射。因此，鼓励配制具有成本效益的口服药物。在当前的研究中，我们评估了小分子 RANKL 抑制剂 A52676293 对转基因 FD 小鼠模型的影响。 A52676293 有效抑制破骨细胞生成并阻止 FD 进展。施用 A52676293 两周后，先前存在的骨缺损主要被新形成的矿化骨所取代。有效的 RANKL 抑制作用和更简单的递送途径使 A52676293 成为 FD 的有前途的靶向治疗药物。我们的研究结果表明，RANKL 抑制可有效阻止 FD 进展并促进骨再矿化，这可能使早发 FD 的患者受益。
Fibrous dysplasia (FD) is a rare bone disease caused by GNAS mutation in skeletal stem cells, typically originating from and worsening in childhood. Till now, no cure for FD exists despite the well-recognized etiology. Studies have demonstrated that osteoclastogenesis hyperactivity is caused by elevated RANKL expression, making RANKL inhibition a potential therapy. Although a human monoclonal anti-RANKL antibody, denosumab, has been used in FD patients, the effects and mechanisms of RANKL inhibition for FD treatment require assessment. Denosumab is expensive and can only be injected. Therefore, formulating an oral-administered, cost-effective medicine is encouraged. In the current study, we evaluated the effects of a small-molecule RANKL inhibitor, A52676293, on a transgenic FD mouse model. A52676293 effectively suppressed osteoclastogenesis and halted FD progression. The pre-existing bone defects were primarily replaced by newly formed mineralized bone after two weeks of A52676293 administration. The potent RANKL inhibitory effect and easier route of delivery make A52676293 a promising target therapy of FD. Results from our study suggested that RANKL inhibition is effective in halting FD progression and promoting bone remineralization, which could benefit the patients with early onset of FD.