A Novel Therapeutic Target for OA that Restores IGF-1 Responses

描述（由申请人提供）：我们研究的长期目标是开发一种有效的治疗骨关节炎（OA）的方法。目前还没有有效的OA治疗方法，OA治疗的潜在市场估计为每年100亿美元。迄今为止，开发用于OA的疾病修饰药物（DMOAD）的努力集中在抑制被认为在OA发展中起关键作用的特定细胞因子（例如IL-1）的活性，或直接抑制降解软骨基质的几种酶中的一种。很少考虑刺激基质合成的药物，尽管这些药物可以减缓基质的逐渐损失，甚至刺激已经受损的软骨的修复。尽管OA关节的修复反应受到刺激，但最近的研究表明，在局灶性软骨退变区域，基质基因的表达存在局部减少，这表明合成能力的丧失是退变过程的关键因素。这种基质合成受损不能用合成代谢生长因子水平不足来解释，因为OA关节中IGF-1和BMP-2的表达升高，特别是在病变区域。更可能的解释是，软骨细胞不能再对这些因素作出反应。随着年龄的增长，软骨细胞失去了对IGF-1的反应能力，人和猴子OA软骨细胞对IGF-1的合成代谢作用的反应有限。因此，任何能够恢复生长因子对软骨细胞敏感性的因子都具有治疗OA的新潜力。IL-1和其他在OA关节中表达升高的细胞因子可在培养软骨细胞中诱导生长因子抵抗。我们已经从80多种已知的抑制剂中确定了两种信号转导抑制剂，它们可以完全恢复IGF-1对IL-1处理的软骨细胞的反应。这两种抑制剂的主要靶点是相同的；然而，具有相同特异性的其他抑制剂不能恢复IGF-1反应的事实表明，必须涉及次要靶点。因此，本I期计划的目标是：a)使用siRNA敲低方法确定这个独特的靶点；b)确定这个靶点是否作为IGF-1合成代谢反应的全局负调节因子；c)确定这些抑制剂中的一种是否可以刺激OA关节退行性区域的修复，使用OA大鼠模型。公共卫生相关性：目前，骨关节炎（OA）没有有效的治疗方法，这是一种严重的使人衰弱的疾病，影响大约50%的65岁以上的人。我们的目标是开发一种新的治疗药物，可以刺激OA关节受损软骨的修复。

DESCRIPTION (provided by applicant): The long-term goal of our research is to develop an effective treatment for osteoarthritis (OA). There is no effective treatment for OA, and the potential market for an OA therapy has been estimated to be $10 billion annually. To date, efforts to develop a disease modifying drug (DMOAD) for OA have focused either on inhibiting the activity of a specific cytokine that is thought to play a pivotal role in the development of OA (e.g. IL-1), or direct inhibition of one of the several enzymes that degrade the cartilage matrix. Very little consideration has been given to agents that stimulate matrix synthesis despite the fact that such agents could slow the progressive loss of matrix and even stimulate repair of already damaged cartilage. Although a repair response is stimulated in OA joints, recent studies show that there is a localized decrease in the expression of matrix genes in regions of focal cartilage degeneration, indicating that loss of synthetic capacity is a critical element of the degenerative process. This impaired matrix synthesis cannot be explained by insufficient levels of anabolic growth factors as there is elevated expression of IGF-1 and BMP-2 in the OA joint, particularly in the lesioned areas. The more likely explanation is that the chondrocytes can no longer respond to these factors. Chondrocytes lose their ability to respond to IGF-1 with age, and human and monkey OA chondrocytes show a limited response to the anabolic effects of IGF-1. Therefore, any factor that could restore growth factor sensitivity to chondrocytes would have novel therapeutic potential for the treatment of OA. Growth factor resistance can be induced in cultured chondrocytes by IL-1 and other cytokines whose expression is elevated in the OA joint. We have identified two signal transduction inhibitors, from over 80 known inhibitors that were screened, that can completely restore the IGF-1 response to IL-1 treated chondrocytes. The primary target for these two inhibitors is the same; however, the fact that other inhibitors with the same specificity cannot restore the IGF-1 response indicates that a secondary target must be involved. Therefore, the objectives of this Phase I proposal are to a) identify this unique target using a siRNA knockdown approach, b) determine whether this target functions as a global negative modulator of IGF-1 anabolic responses and c) determine whether one of these inhibitors can stimulate repair in degenerative regions of an OA joint using a rat model of OA. PUBLIC HEALTH RELEVANCE: Currently, there is no effective treatment for osteoarthritis (OA), a severely debilitating disease that affects approximately 50% of those over 65 years of age. Our goal is to develop a novel therapeutic drug that can stimulate repair of damaged cartilage in the OA joint.