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

描述（由申请人提供）：骨关节炎（OA）是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。直到需要关节置换的疾病的终末期才有有效的治疗OA的方法。尽管对OA晚期关节软骨退变的研究取得了显著进展，但对OA发病机制的研究却知之甚少。目前，大多数研究OA关节软骨退变机制的努力都是在OA的晚期阶段。在这个修订后的建议，我们已经证明，诱导敲除TGF？巢蛋白+间充质干细胞的II型受体可防止小鼠前交叉韧带横断（ACLT）关节的关节软骨退化;抗体在软骨下骨减少大鼠ACLT关节和全身注射T？RI抑制剂也可挽救豚鼠自发性OA。这些结果表明，高水平的活性TGF？1是ACLT动物模型、豚鼠自发性OA和人膝OA的发病病理变化。特别是，保护豚鼠自发性OA的T？RI抑制剂整合高水平的活性TGF？骨关节炎患者膝关节软骨下骨的骨密度和ACLT动物模型的数据。因此，激活TGF？在软骨下骨中出现的异常代表OA发展的开始。因此，特异性抑制TGF？活动在软骨下骨可能导致一种有效的治疗， OA。因此，我们假设，高水平的活性TGF？诱发OA的病理改变。在这项拟议的研究中，我们将重点关注OA发展过程中的初始事件，并将研究TGF？采用诱导型nestin/cre/GFP/ROSA 26或osterix/cre/GFP/ROSA 26小鼠，观察诱导型nestin+ MSCs和osterix+骨祖细胞微环境改变对骨软骨连接的影响，并追踪ACLT小鼠OA发生过程中GFP阳性nestin+ MSCs和osterix+骨祖细胞的变化。我们还将研究TGF？在人OA膝关节的软骨下骨和关节软骨中。抑制TGF？将系统研究大鼠ACLT OA和自发豚鼠OA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.