载siRNA磁性脂质体体内靶向抑制假体周围炎性微环境内破骨细胞RANK/RANKL途径的研究

批准号:
81201416
项目类别:
青年科学基金项目
资助金额:
23.0 万元
负责人:
吴浩波
依托单位:
学科分类:
H0606.骨、关节、软组织感染
结题年份:
2015
批准年份:
2012
项目状态:
已结题
项目参与者:
何荣新、赵翔、师钟丽、应志敏、钟诚、史明敏、郁肖夫
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中文摘要
正常的骨代谢有赖于骨吸收和骨形成之间的相互平衡。在人工关节领域,由聚乙烯磨损微粒为首介导的生物学反应可以在局部大量激活以破骨细胞为主的巨噬细胞系统,从而在人工关节部件周围造成大量的骨溶解,这也是假体远期失败的最主要的原因,也称之为"微粒病"或又称为"假体周围炎性微环境相关性骨溶解"。RANK/RANKL途径是目前已知引起破骨细胞激活的主要信号途径。本研究拟将RANK单克隆抗体与脂质体结合形成免疫脂质体,并使用载siRNA磁性脂质体技术靶向抑制假体周围破骨细胞激活的RANK/RANKL途径来治疗假体周围骨溶解疾病。本方法存在以下优点:第一, siRNA不破坏目标细胞的DNA结构,没有潜在的致突变性等风险。第二,靶向定位可以使siRNA抑制破骨细胞更有针对性,减少全身反应。第三,siRNA的研制技术目前已经基本成熟。本研究具有良好的研究基础,足以完成该项研究。
英文摘要
The balance between bone resorption and formation keeps the dynamic integrity of the whole bone. Such balance is determined by the interaction between osteoclast and osteoblast. In artificial arthroplasty field, polyethylene particles would induce local osteoclast activation and cause periprothetic osteolysis. This phenomenon is called "particles disease". Nowadays, the approaches for treatment and prevention of osteolysis are divided into two groups: 1, reducing the production of wear particles; 2, blocking the osteolysis process and restoring the bone anabolic balance. Various methods have been introduced to solve this problem, such as bisphosphonates. However, bisphosphonates may lead into some complications, such as over-inhibition of bone metabolism(frozen bone). Lone-time usage of bisphosphonate, especially over 5 years, is not recommended in clinical practice. . In the year of 2008, NFATc1 specific siRNA was reported to inhibit mouse osteoclast activation. SiRNA can effectively bind with special mRNA and silence special genes and take effects in an extremely small amount. More importantly, it would not completely silence osteoclast, keeping the function of osteoclast in certain low level and avoiding over-inhibition. . The immunoliposome technique is another important immune-targeted technique. It packages drugs or monoclonal antibodies with liposome. These drugs or antibodies would be released into the targeted cells and affect their functions. If magnetic material is introduced into such liposomes, the magnetic immunoliposome could be guided by the direction of magnetic field to the targeted organs, which is of great importance in clinical practice. This technique has been matured recently and it is now broadly applied. Additional, our research team successfully produced spherical hydroxyapatite particles with the diameter of 20-nm(20HA) in our previous research. Our 20HA has the advantage to induce maturation and differentiation of stromal cells and osteoblast, and regulate mineral process of the cell. This paper is regarded by China Science and Technology Information Institute to be one of the 100 best study papers in China. In our program, our research aims to mix iron oxide, pore-forming agent and 20HA together to form a new material. This material could be sprayed over the prosthesis and forming a magnetic 20HA coating. Such magnetic coating would attract the magnetic liposome aggregated around the prosthesis. This could effectively reduce the systemic side effects of the liposome. . The RANK/RANKL signal approach is the main known mechanism to activate osteoclast. Our study aims to mix anti-RANK antibody and liposomes together, and uses siRNA loaded magnetic liposome technique to make targeted inhibition on periprosthetic osteoclast. We consider, this would significantly inhibit local osteoclast activity and reduce the periprosthetic osteolysis.
正常的骨代谢有赖于骨吸收和骨形成之间的相互平衡。在人工关节领域,由聚乙烯磨损微粒为首介导的生物学反应可以在局部大量激活以破骨细胞为主的巨噬细胞系统,从而在人工关节部件周围造成大量的骨溶解,这也是假体远期失败的最主要的原因,也称之为“微粒病”或又称为“假体周围炎性微环境相关性骨溶解”。研究结果显示微粒病中导致骨溶解的具体机制非常复杂,RANK/RANKL 途径是目前已知引起破骨细胞激活的主要信号途径。目前的免疫脂质体已具有制备工艺简便,无毒、无免疫原性及可被生物膜利用的特点,它携带、保护及释放药物的能力高于单克隆抗体,是现阶段抗体靶向治疗的研究热点,但在抗骨质疏松领域特别是抑制破骨细胞功能方面,尚未见到报导。. 在本次研究中,我们建立了成骨细胞、破骨细胞离体磨损颗粒骨溶解复合体模型的建立并进行鉴定,用siRNA抑制RANK对成骨细胞、破骨细胞离体磨损颗粒骨溶解复合体模型,观察其对细胞功能的影响并探索机制,建立兔股骨远端颗粒诱导骨溶解模型的建立,用载siRNA 脂质体靶向治疗预防股骨远端骨溶解发生。. 通过我们的研究发现,RANK siRNA可以通过明显抑制OPG/RANK/RANKL信号通路,抑制体外成骨细胞、破骨细胞离体磨损颗粒骨溶解复合体模型中破骨细胞的形成, Raw264.7细胞增值,促进Raw264.7细胞和破骨细胞凋亡以及迁移,促进细胞的碱性磷酸酶(ALP)和抑制 抗酒石酸酸性磷酸酶 (TRAP)的分泌,从而降低体外假体松动的发生。我们也通过兔关节腔注射RANK siRNA脂质体,成功的预防了假体松动的发生。. 我们的研究成过的抗骨丢失性能可以广泛的用于骨质疏松和各种骨溶解症的治疗,并且在人工关节领域可以预防和治疗微粒病的发生,解决松动失败的问题,延长假体寿命,因此具有非常重要的临床应用价值和前景,并具有巨大的社会意义和经济价值。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Combined use of extensively porous coated femoral components with onlay cortical strut allografts in revision of Vancouver B2 and B3 periprosthetic femoral fractures
结合使用广泛多孔涂层股骨组件与同种异体骨皮质支撑移植物修复温哥华 B2 和 B3 假体周围股骨骨折
DOI:10.3760/cma.j.issn.0366-6999.2009.21.016
发表时间:2009-11-05
期刊:CHINESE MEDICAL JOURNAL
影响因子:6.1
作者:Wu Hao-bo;Yan Shi-gui;Dai Xue-song
通讯作者:Dai Xue-song
Short reconstruction nail for intertrochanteric fracture: does it really fit Asian feature?
股骨粗隆间骨折短重建钉:真的适合亚洲人特征吗?
DOI:10.1007/s00402-011-1365-7
发表时间:2011
期刊:Archives of Orthopaedic and Trauma Surgery
影响因子:2.3
作者:Zhao, Xiang;Yan, Shi-Gui;Li, Hang;Wu, Hao-Bo
通讯作者:Wu, Hao-Bo
DOI:10.3892/ijmm.2012.1192
发表时间:2013
期刊:International journal of molecular medicine
影响因子:5.4
作者:Zeng-Feng Xin;Cheng-chun Shen;Li-jiang Tao;Shi-gui Yan;Hao-bo Wu
通讯作者:Zeng-Feng Xin;Cheng-chun Shen;Li-jiang Tao;Shi-gui Yan;Hao-bo Wu
Microbubble-mediated ultrasound enhances the lethal effect of gentamicin on planktonic Escherichia coli.
微生物介导的超声可以增强庆大霉素对浮游大肠杆菌的致命作用。
DOI:10.1155/2014/142168
发表时间:2014
期刊:BioMed research international
影响因子:--
作者:Zhu HX;Cai XZ;Shi ZL;Hu B;Yan SG
通讯作者:Yan SG
MICROBUBBLE INJECTION ENHANCES INHIBITION OF LOW-INTENSITY PULSED ULTRASOUND ON DEBRIS-INDUCED PERIPROSTHETIC OSTEOLYSIS IN RABBIT MODEL
微泡注射增强了低强度脉冲超声对兔模型碎片引起的假体周围骨溶解的抑制作用。
DOI:10.1016/j.ultrasmedbio.2014.08.016
发表时间:2015-01-01
期刊:ULTRASOUND IN MEDICINE AND BIOLOGY
影响因子:2.9
作者:Hu, Bin;Cai, Xun-Zi;Yan, Shi-Gui
通讯作者:Yan, Shi-Gui
机械应力丢失通过下调KLF15-UCP2轴激活成纤维脂肪祖细胞成脂分化介导肩袖撕裂后肌肉脂肪浸润及其机制研究
- 批准号:82372487
- 项目类别:面上项目
- 资助金额:49万元
- 批准年份:2023
- 负责人:吴浩波
- 依托单位:
IGF-1缓释蚕丝组织工程支架促进肩袖肌腱修复再生作用及其机制研究
- 批准号:81972077
- 项目类别:面上项目
- 资助金额:55.0万元
- 批准年份:2019
- 负责人:吴浩波
- 依托单位:
国内基金
海外基金
