Abstract:
Osteolytic bone disease is a condition of imbalanced bone homeostasis, characterized mainly by excessive bone-resorptive activity, which could predispose these populations, such as the old and postmenopausal women, to developing high risk of skeletal fragility and fracture. The nature of bone homeostasis is the coordination between the osteoblasts (OBs) and osteoclasts (OCs). Abnormal activation of osteoclasts (OCs) could compromise the bone homeostasis, constantly followed by a clutch of osteolytic diseases, including postmenopausal osteoporosis, osteoarthritis, and rheumatoid arthritis. Thus, it is imperatively urgent to explore effective medical interventions for patients. The traditional Chinese medicine (TCM) gamabufotalin (CS-6) is a newly identified natural product from Chansu and has been utilized for oncologic therapies owing to its good clinical efficacy with less adverse events. Previous study suggested that CS-6 could be a novel anti-osteoporotic agent. Nevertheless, whether CS-6 suppresses RANK-(receptor activator of nuclear factor-κ B ligand)/TRAF6 (TNF receptor-associated factor 6)-mediated downstream signaling activation in OCs, as well as the effects of CS-6 on OC differentiation in vivo, remains elusive. Therefore, in this present study, we aimed to explore the biological effects of CS-6 on osteoclastogenesis and RANKL-induced activation of related signaling pathways, and further to examine the potential therapeutic application in estrogen-deficient bone loss in the mice model. The results of in vitro experiment showed that CS-6 can inhibit RANKL-induced OC formation and the ability of bone resorption in a dose-dependent manner at both the early and late stages of osteoclastogenesis. The gene expression of OC-related key genes such as tartrate-resistant acid phosphatase (TRAP), CTSK, DC-STAMP, MMP9, and β3 integrin was evidently reduced. In addition, CS-6 could mitigate the systemic estrogen-dependent bone loss and pro-inframammary cytokines in mice in vivo. The molecular mechanism analysis suggested that CS-6 can suppress RANKL/TRAF6-induced early activation of NF-κB and ERK/MAPK signaling pathways, which consequently suppressed the transcription activity of c-Fos and NFATc1. Taken together, this present study provided ample evidence that CS-6 has the promise to become a therapeutic candidate in treating osteolytic conditions mediated by elevated OC formation and bone resorption.
摘要:
溶骨性骨病是骨稳态失衡的一种疾病,主要以过度的骨吸收活动为特征,这可能会使这些人群易感,比如老年和绝经后的妇女,发展骨骼脆性和骨折的高风险。骨稳态的本质是成骨细胞(OB)和破骨细胞(OC)之间的协调。破骨细胞(OCs)的异常激活可能损害骨稳态,不断伴随着一系列溶骨疾病,包括绝经后骨质疏松症,骨关节炎,和类风湿性关节炎。因此,迫切需要探索有效的患者医疗干预措施。中药(TCM)gamabufotalin(CS-6)是来自Chansu的新鉴定的天然产品,由于其良好的临床疗效和较少的不良事件,已用于肿瘤治疗。先前的研究表明,CS-6可能是一种新型的抗骨质疏松剂。然而,CS-6是否抑制RANK-(核因子-κB配体的受体激活剂)/TRAF6(TNF受体相关因子6)介导的OCs下游信号激活,以及CS-6在体内对OC分化的影响,仍然难以捉摸。因此,在本研究中,本研究旨在探讨CS-6对破骨细胞生成和RANKL诱导的相关信号通路激活的生物学效应,并进一步检查在小鼠模型中雌激素缺乏的骨丢失中的潜在治疗应用。体外实验结果表明,CS-6可以在破骨细胞形成的早期和晚期以剂量依赖的方式抑制RANKL诱导的OC形成和骨吸收能力。OC相关关键基因如抗酒石酸酸性磷酸酶(TRAP)的基因表达,CTSK,DC-STAMP,MMP9和β3整合素明显减少。此外,CS-6可以减轻小鼠体内全身性雌激素依赖性骨丢失和乳腺前细胞因子。分子机制分析提示CS-6可抑制RANKL/TRAF6诱导的NF-κB和ERK/MAPK信号通路的早期激活,从而抑制c-Fos和NFATc1的转录活性。一起来看,本研究提供了充分的证据,表明CS-6有望成为治疗由OC形成和骨吸收升高介导的溶骨疾病的候选药物。