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。在这项修订的建议中，我们证明了在Nestin+MSCs中可诱导地敲除转化生长因子受体II型受体可防止小鼠前十字韧带横断(ACLT)关节的关节软骨退变；在软骨下注射转化生长因子β抗体可减少大鼠前交叉韧带横断(ACLT)关节的关节软骨退变；系统注射TüRI抑制剂也可挽救豚鼠自发性骨关节炎。这些结果表明，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骨性骨性关节炎的病理改变。特别是，TüRI抑制剂对豚鼠自发性骨性关节炎的保护作用结合了对骨性关节炎患者膝关节软骨下骨中高水平活性转化生长因子的观察和来自ACLT动物模型的数据。因此，软骨下骨中转化生长因子的激活代表了骨性关节炎发展的开始。因此，特异性地抑制软骨下骨中转化生长因子的活性可能会导致有效的治疗 骨关节炎。因此，我们推测软骨下骨中高水平的活性转化生长因子引起了骨性关节炎的病理改变。在这项拟议的研究中，我们将重点关注骨关节炎发育过程中的初始事件，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ç诱导的MSCs和骨祖细胞微环境变化对骨软骨连接变化的影响，其中GFP阳性的Nestin+MSCs和Osterix+骨祖细胞将在ACLT小鼠的骨关节发育过程中进行追踪。我们还将研究转化生长因子在人膝关节骨关节炎软骨下骨和关节软骨中的作用。我们将系统地研究抑制软骨下骨中转化生长因子的活性对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的影响。

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 TGFß type II receptor in the nestin+ MSCs prevents degeneration of articular cartilage in the mouse anterior cruciate ligament transection (ACLT) joints; administration of TGFß antibody in the subchondral bone reduces articular cartilage degeneration in rat ACLT joints and systemically injection of TßRI inhibitor also rescued guinea pig spontaneous OA. These results suggest that high levels of active TGFß1 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 TßRI inhibitor integrate the observation of high levels of active TGFß in the subchondral bone in the knee joints of OA patient and the data from ACLT animal models. Thus, activation of TGFß in the subchondral bone represents onset of OA development. Thus, specific inhibition of TGFß activity in the subchondral bone could lead to an effective therapy for OA. Therefore, we hypothesize that high levels of active TGFßin 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 TGFß-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 TGFß in the subchondral bone and articular cartilage of human OA knee joints. The effects of inhibition of TGFß activity in the subchondral bone on rat ACLT OA and spontaneous guinea pig OA joints will be systematically studied.