Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Orthopedic Research Institute of Zhejiang University, Hangzhou, China.
Br J Pharmacol. 2018 Mar;175(6):859-876. doi: 10.1111/bph.14092. Epub 2018 Feb 14.
Aseptic prosthesis loosening, caused by wear particles, is one of the most common causes of arthroplasty failure. Extensive and over-activated osteoclast formation and physiological functioning are regarded as the mechanism of prosthesis loosening. Therapeutic modalities based on inhibiting osteoclast formation and bone resorption have been confirmed to be an effective way of preventing aseptic prosthesis loosening. In this study, we have investigated the effects of sophocarpine (SPC, derived from Sophora flavescens) on preventing implant loosening and further explored the underlying mechanisms.
The effects of SPC in inhibiting osteoclastogenesis and bone resorption were evaluated in osteoclast formation, induced in vitro by the receptor activator of NF-κB ligand (RANKL). A rat femoral particle-induced peri-implant osteolysis model was established. Subsequently, micro-CT, histology, mechanical testing and bone turnover were used to assess the effects of SPC in preventing implant loosening.
In vitro, we found that SPC suppressed osteoclast formation, bone resorption, F-actin ring formation and osteoclast-associated gene expression by inhibiting NF-κB signalling, specifically by targeting IκB kinases. Our in vivo study showed that SPC prevented particle-induced prosthesis loosening by inhibiting osteoclast formation, resulting in reduced periprosthetic bone loss, diminished pseudomembrane formation, improved bone-implant contact, reduced bone resorption-related turnover and enhanced stability of implants. Inhibition of NF-κB signalling by SPC was confirmed in vivo.
SPC can prevent implant loosening through inhibiting osteoclast formation and bone resorption. Thus, SPC might be a novel therapeutic agent to prevent prosthesis loosening and for osteolytic diseases.
由磨损颗粒引起的无菌性假体松动是关节置换失败的最常见原因之一。广泛和过度激活的破骨细胞形成和生理功能被认为是假体松动的机制。基于抑制破骨细胞形成和骨吸收的治疗方式已被证实是预防无菌性假体松动的有效方法。在本研究中，我们研究了苦参碱（SPC，来源于苦参）在预防假体松动中的作用，并进一步探讨了其潜在机制。
通过核因子-κB 受体激活物配体（RANKL）体外诱导破骨细胞形成，评估 SPC 抑制破骨细胞形成和骨吸收的作用。建立大鼠股骨颗粒诱导的种植体周围骨溶解模型。随后，采用微 CT、组织学、力学测试和骨转换来评估 SPC 预防假体松动的作用。
体外实验发现，SPC 通过抑制 NF-κB 信号通路，特别是通过靶向 IκB 激酶，抑制破骨细胞形成、骨吸收、F-actin 环形成和破骨细胞相关基因表达，从而抑制破骨细胞形成。体内研究表明，SPC 通过抑制破骨细胞形成，防止颗粒诱导的假体松动，从而减少假体周围骨丢失，减少假膜形成，改善骨-假体接触，减少与骨吸收相关的骨转换，增强假体的稳定性。体内实验证实了 SPC 对 NF-κB 信号通路的抑制作用。
SPC 可通过抑制破骨细胞形成和骨吸收来预防假体松动。因此，SPC 可能是一种预防假体松动和溶骨性疾病的新型治疗药物。
