TGFβ1介导软骨下骨骨重塑在OA病变中的机制与作用研究

Knee osteoarthritis（KOA）is a chronic arthropathy that seriously affected locomotion of the quinquagenarian. KOA’s clinical diagnosis and treatment have been a great puzzle due to the indefinity of its nosogenesis. Recent studies have shown that both cartilaginous tissue and subchondral bone play important roles in OA affection, but investigations on the control mechanism correlating to the two factors are very few. Our preliminary study found that, the appearance of early OA clinical symptoms is attributed to a series of mechanisms： Transforming Growth Factor β（TGFβ1）induced the ossification of uncoupled subchondral bone which led to the alteration at the junction between bone and cartilage. The incrassation of subchondral bone led to the hypertrophy of cartilage cell and the cataplasis of arthrodial cartilage. Thus, we presume that the development of OA may be effectively prevented through applying TGFβ1 suppressor..Based on this assumption ,our research plans to observe the influence of it in OA affection through detecting the dependency relation among structural change in subchondral bone, activity of TGFβ1,and cartilage catabolic enzymes in different OA lesions cycle; constructing ACLT-OA model of SD rat and spontaneous OA model of cavia, local injecting TGFβ1 depressor into articular subchondral bone.The study above may reveal the pathomechanism of TGFβ1 in OA affection, provid New theoretical and experimental basis for targeted therapy, and explore innovation for the clinical treatment of OA.

膝骨关节炎（KOA）已成为严重影响中老年行动的慢性关节病变，由于发病机制不明，给临床诊治带来了极大的困难。近年来研究表明软骨组织和软骨下骨在OA病变中均发挥重要的作用，目前关于二者之间的相关调控机制研究较少，我们的前期研究发现转化生长因子β（TGFβ1）诱导了非偶联的软骨下骨成骨，进而导致骨与软骨连接处的改变，软骨下骨的增厚导致了软骨细胞的肥大和关节软骨的退变，临床出现早期OA的症状。因此我们推测应用TGFβ1抑制剂可有效阻止OA的发展。基于此假设，本研究拟通过检测不同OA病变周期中软骨下骨结构改变、TGFβ1的活性及其与软骨降解酶等之间的相关关系；同时构建SD大鼠ACLT-OA模型和豚鼠自发性OA模型，应用TGFβ1抑制剂进行关节软骨下骨局部注射，观察其对OA病变的影响。从而揭示TGFβ1在OA病变中的病理机制，为OA的靶向治疗提供新的理论和实验依据，为临床OA的治疗探索新方法。

膝骨关节炎（KOA）是一种严重影响中老年膝关节功能的慢性关节病变，目前其病因学机制不明，给临床诊治带来了极大的困难。我们的的研究发现转化生长因子β（TGFβ1）诱导了非偶联的软骨下骨成骨，进而导致骨与软骨连接处的改变，软骨下骨的增厚导致了软骨细胞的肥大和关节软骨的退变，临床出现早期OA的症状。本次研究对行膝关节置换的105例胫骨平台及6例截肢的正常软骨胫骨平台作为研究对象，对内侧软骨剥脱区，内侧软骨破坏区，外侧软骨完整区和正常膝关节炎内侧平台区域进行uCT扫描，结果显示在内侧软骨剥脱区和内侧软骨破坏区，BV/TV, Modulus, P-R ratio, pBV/TV, pTb.Th, pTb.N, rBV/TV, rTb.Th, rTb.N较对照组明显增高（所有p<0.05 ）。在外侧软骨完整区，rTb.N较对照明显减少（p=0.013），而pTb.Th较对照组明显增高（p=0.028）。免疫组化结果显示，软骨退变严重区域MMP-3、MMP-13、IL-1β的表达均显著降低，与正常软骨区差异不明显，而TGFβ1、β-catenin和pSmad1的表达显著高于对照组。而软骨退变轻区MMP-3、MMP-13、IL-1β的表达最高，与正常软骨区、退变严重区差异显著。另外TGFβ1、MMP-3、MMP-13和IL-1β mRNA的表达水平也与上述结果一直。结果表明：细胞因子及降解酶参与软骨的降解，在软骨下骨的退变中也发挥着极其重要的作用. 通过本次研究，我们明确TGFβ1在软骨下骨的硬化中起关键作用，抑制TGFβ1表达可能是防治软骨下骨硬化的重要方法。今后开发出针对TGFβ1靶向药物，在OA的治疗中有着重要的临床价值。