TGF-beta Activity in the Subchondral Bone and Onset of OA

描述(申请人提供)：骨关节炎(OA)是导致身体残疾的主要原因，预计到2030年将影响美国6700万人，是最常见的退行性关节疾病。直到疾病的末期需要关节置换术，才能有效治疗骨性关节炎。尽管关节软骨退行性变在相对较晚的骨性关节炎的研究中取得了显著进展，但对其发病机制仍知之甚少。目前，对骨性关节炎关节软骨退变机制的研究大多处于骨性关节炎的晚期。在这个修订的方案中，我们证明了诱导敲除Nestin+MSCs中的转化生长因子受体II型受体可以防止小鼠前交叉韧带横断(ACLT)关节的关节软骨退变。软骨下抗体可减轻大鼠ACLT关节软骨退变，全身注射T？RI抑制剂对豚鼠自发性骨关节炎也有一定的保护作用。这些结果提示，软骨下骨中高水平的活性转化生长因子-1是ACLT动物模型、豚鼠自发性骨性关节炎和人膝关节骨性关节炎的发病病理改变。尤其是T？RI抑制剂对豚鼠自发性骨性关节炎的保护作用结合了对高水平活化的转化生长因子？骨关节炎患者膝关节软骨下骨和ACLT动物模型的数据。因此，转化生长因子的激活？在软骨下骨中代表了骨性关节炎的开始。因此，特异性抑制转化生长因子？软骨下骨的活动可能导致一种有效的治疗方法 骨关节炎。因此，我们假设高水平的活性转化生长因子？在软骨下骨中诱导骨关节炎的病理改变。在这项拟议的研究中，我们将重点关注骨关节炎发生过程中的初始事件，并将利用可诱导的Nestin/cre/GFP/rosa26或Osterix/cre/GFP/rosa26小鼠，研究转化生长因子β诱导的间充质干细胞和骨祖细胞微环境的改变对骨软骨连接变化的影响，以追踪GFP阳性的Nestin+MSCs和Osterix+骨祖细胞在ACLT小鼠骨软骨发育过程中的变化。我们还将研究转化生长因子的作用？在人膝骨关节炎的软骨下骨和关节软骨中。抑制转化生长因子的作用？我们将系统地研究大鼠前交叉韧带骨性关节炎和豚鼠自发性骨性关节炎关节软骨下骨的活性。

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the leading cause of physical disability, predicted to affect 67 million people in the United States by 2030 and is the most common degenerative joint disorders. There is no effective treatment for OA until the end-stage of the disease necessitating joint replacement. Despite the significant progress made in the investigation of articular cartilage degeneration at relative late stage of OA, little is known abot the onset pathomechanisms of OA. Currently, most of the efforts that are investigating the mechanism of articular cartilage degeneration in OA are in the late stage of OA. In this revised proposal, we have demonstrated that inducible knockout of TGF?type II receptor in the nestin+ MSCs prevents degeneration of articular cartilage in the mouse anterior cruciate ligament transection (ACLT) joints; administration of TGF? antibody in the subchondral bone reduces articular cartilage degeneration in rat ACLT joints and systemically injection of T?RI inhibitor also rescued guinea pig spontaneous OA. These results suggest that high levels of active TGF?1 in the subchondral bone are the onset pathological changes in ACLT animal models, guinea pig spontaneous OA and human knee OA. Particularly, protection of guinea pig spontaneous OA by T?RI inhibitor integrate the observation of high levels of active TGF? in the subchondral bone in the knee joints of OA patient and the data from ACLT animal models. Thus, activation of TGF? in the subchondral bone represents onset of OA development. Thus, specific inhibition of TGF? activity in the subchondral bone could lead to an effective therapy for OA. Therefore, we hypothesize that high levels of active TGF? in the subchondral bone induce pathological changes of OA. In this proposed study, we will focus on the initial events during development of OA and will investigate the effects of TGF?-induced microenvironment changes of MSCs and osteoprogenitors on the changes of osteochondral junction using inducible nestin/cre/GFP/ROSA26 or osterix/cre/GFP/ROSA26 mice, in which the changes of GFP-positive nestin+ MSCs and osterix+ osteoprogenitors will be traced during development of OA in ACLT mice. We will also examine the role of TGF? in the subchondral bone and articular cartilage of human OA knee joints. The effects of inhibition of TGF? activity in the subchondral bone on rat ACLT OA and spontaneous guinea pig OA joints will be systematically studied.