超声靶向他汀微泡保护骨关节炎软骨的胆固醇逆转运调控机制研究

Reverse cholesterol transport plays an important role in OA cartilage degeneration.It is the only way that chondrocytes get rid of excess cholesterol and keep cholesterol balance. Statins is a kind of cholesterol-lowering drugs, has been confirmed with cartilage protection, but not used in the clinical treatment of OA because of the large oral side effects. Ultrasound (US) targeted drug-microbubble destruction is a kind of new cures for US and can be used to increase the intra-articular injection effects of statin. Our previous studies have found that the expression of type II collagen, reverse cholesterol transport regulatory factor PPARγ, and the rate of cholesterol efflux in OA chondrocytes was decreased, and the application of US targeted statin-microbubble increased OA chondrocytes cholesterol efflux and the expression of the above factors. Thus we speculate that US targeted statin-microbubble may protect cartilage by promoting reverse cholesterol transport of OA chondrocytes.This study will explore the correlation of OA cartilage degeneration with reverse cholesterol transport and the effects of US targeted statin-microbubble intervention in vivo, vitro and molecular level. We will use signaling molecule inhibition technology to clarify the cartilage protection mechanism of US targeting statin microbubble promotes OA chondrocytes reverse cholesterol transport, inhibit degradation of extracellular matrix by PPAR γ/LXR/ABCA1 signaling pathway.This study will provide new ideas and evidence for the US and statins treatment of OA.

胆固醇逆转运在骨关节炎（OA）软骨退变中扮演重要角色，是软骨细胞排出多余胆固醇，维持胆固醇平衡的主要途径。他汀是一类降胆固醇药物，具有软骨保护作用，但因口服副作用大，尚未用于OA临床治疗。超声（US）靶向载药微泡破裂是一种US治疗新方法，可增强他汀关节腔内用药效果。本课题组前期研究发现，OA软骨细胞II型胶原、胆固醇逆转运调控因子PPARγ表达和胆固醇流出率下降，US靶向他汀微泡可提高上述因子表达和胆固醇流出率，延缓软骨退变，提示US靶向他汀微泡可能通过促进OA软骨细胞胆固醇逆转运产生软骨保护作用。本课题拟在整体、细胞和分子水平上探讨OA软骨退变与胆固醇逆转运的相关性及US靶向他汀微泡的干预作用，通过分子抑制技术拟证明US靶向他汀微泡经PPARγ/LXR/ABCA1信号通路促进OA软骨细胞胆固醇逆转运，从而抑制细胞外基质降解的软骨保护机制，为US和他汀类药物用于OA治疗提供新的方法和依据。

胆固醇逆转运障碍是骨关节炎（OA）软骨退变的重要原因之一。他汀类药物是常用的降胆固醇药物，已经被证明具有软骨保护作用，但由于口服副作用大，目前还没有在临床上用于OA的治疗。超声靶向载药微泡破裂是一种超声新技术，通过微泡的传递能够增强药物在局部的治疗作用。本研究探讨了OA软骨退变与胆固醇逆转运的相关性及超声靶向他汀微泡经PPARγ介导的胆固醇逆转运信号通路保护OA软骨的作用机制。研究结果发现OA软骨细胞存在脂质沉积，胆固醇流出率明显下降，细胞外基质蛋白表达减少，辛伐他汀可促进OA软骨细胞胆固醇流出，降低脂质沉积，提高细胞外基质蛋白II型胶原、蛋白多糖和胆固醇逆转运调控因子PPARγ、LXRα和ABCA1的表达，同时降低基质降解酶MMP-13的表达。进一步研究发现与单纯辛伐他汀、超声靶向空微泡干预相比，超声靶向辛伐他汀微泡可显著促进OA软骨细胞胆固醇流出，降低脂质沉积，提高软骨细胞外基质蛋白和胆固醇逆转运调控因子的表达，而PPARγ抑制剂会显著降低超声靶向辛伐他汀微泡在OA中的软骨保护作用。以上研究成果证明了超声靶向辛伐他汀微泡促进胆固醇逆转运保护OA软骨的作用机制，为超声靶向辛伐他汀微泡应用于OA的治疗提供了理论依据，有助于超声和辛伐他汀在OA治疗领域的应用推广，同时，我们在研究中所涉及的与胆固醇逆转运相关的信号分子靶点也为今后探索OA新的治疗策略提供了思路。