CHONDROPROTECTION BY A NOVEL RETINOID AND TRITERPENOID

描述（申请人摘要）：风湿性关节炎（RA）和 骨关节炎（OA）是使人衰弱的疾病，其特征在于 关节软骨和骨的进行性退化。虽然病因 这两种疾病是完全不同的，降解成分是 相似之处在于软骨和骨的间质胶原被消化 被一组蛋白水解酶所控制， 金属蛋白酶（MMP）。一个MMP最近卷入了 RA和OA的进展是胶原酶-3或MMP-13。在MMP中，MMP-13是 最有效地降解II型胶原蛋白，即存在于 关节软骨MMP-13在骨关节炎软骨中表达， 类风湿性滑膜，并在软骨细胞中诱导， 与炎性细胞因子白细胞介素-I（IL-1）和肿瘤坏死 因子-α（TNF）。因此，在OA和RA中抑制MMP-13是重要的， 软骨保护治疗的目标。我们发现一种新的类维生素A， BMS-189453抑制小鼠胶原诱导性关节炎中MMP-13的合成 模型我们还证明了一种新的类固醇， 2-氰基-3，12-二氧代-1，9-二烯-28-酸（CDDO），也可抑制MMP-13 在软骨细胞中合成，并具有有效的抗炎特性。在这 应用，我们提出的研究，将定义，在细胞水平上， BMS-189453和CDDO抑制软骨细胞中MMP-13基因表达的机制。 具体来说，这些研究将定义转录因子和信号传导。 转导中间体是这些化合物的靶标。自从类固醇 和维甲酸一起更有效地抑制胶原蛋白降解， 测试BMS-189453和CDDO的组合，看看每种药物的较低剂量是否可以 被利用我们将扩展这项工作，以建立软骨保护功效， STR/ORT自发性研究中BMS-189453和CDDO单用和联合给药的研究 在OA小鼠模型中，以及在胶原诱导的关节炎（CIA）小鼠模型中， RA.我们的目标是确定每种化合物在炎症中的效力， (CIA)和非炎性（STR/ORT）关节炎模型，并评估 联合治疗的潜力，这可能导致治疗更少 副作用.这项工作将检查细胞/分子事件和整个动物 模型来表征一种新的类固醇和一种 用于治疗关节炎的新型类维生素A。

DESCRIPTION (Applicant's abstract): Rheumatoid arthritis (RA) and osteoarthritis (OA) are debilitating disorders that are characterized by progressive degradation of articular cartilage and bone. While the etiologies of these two diseases are quite different, the degradative components are similar in that the interstitial collagens of cartilage and bone are digested by a group of proteolytic enzymes that are collectively known as the matrix metalloproteinases (MMP). One MMP that has been recently implicated in the progression of RA and OA is collagenase-3, or MMP-13. Of the MMPs, MMP-13 is the most efficiently degrades type II collagen, the primary collagen present in articular cartilage. MMP- 13 is expressed in osteoarthritic cartilage and rheumatoid synovium, and is induced in chondrocytes that have been stimulated with the inflammatory cytokines interleukin-l (IL-I) and tumor necrosis factor-alpha (TNF). Thus, inhibition of MMP-13 in OA and RA is an important goal for therapies of chondroprotection. We have found that a novel retinoid, BMS-189453, inhibits MMP-13 synthesis in a mouse collagen-induced arthritis model. We have also demonstrated that a novel steroid, 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid (CDDO), also inhibits MMP-13 synthesis in chondrocytes and has potent anti-inflammatory properties. In this application, we propose studies that will define, on the cellular level, the mechanisms of MMP-13 gene repression in chondrocytes by BMS-189453 and CDDO. Specifically, these studies will define transcription factors and signal transduction intermediates that are targets of these compounds. Since steroids and retinoids inhibit collagen degradation more effectively together, we will test the combination of BMS- 189453 and CDDO, to see if lower doses of each can be used. We will extend this work to establish the chondroprotective efficacy of BMS-189453 and CDDO, alone and in combination, in the STR/ORT spontaneous mouse model of OA, and in the mouse collagen-induced arthritis (CIA) model of RA. Our goals are to establish the potency of each compound in an inflammatory (CIA) and non-inflammatory (STR/ORT) model of arthritis, and assess the potential of combinatorial treatment, which may lead to therapies with fewer side effects. This work will examine cellular/molecular events and whole animal models to characterize the chondroprotective potential of a novel steroid and a novel retinoid for the treatment of arthritis.