CHONDROPROTECTION BY A NOVEL RETINOID AND TRITERPENOID

描述(申请人摘要)：类风湿性关节炎(RA)和 骨关节炎(OA)是一种衰弱的疾病，其特征是 关节软骨和骨的进行性退化。而病因 这两种疾病有很大的不同，降解成分是 相似之处在于软骨和骨骼的间质胶原被消化 由一组蛋白水解酶组成，它们统称为基质 金属蛋白酶(MMPs)。最近发现的一种多发性骨髓瘤 类风湿性关节炎和骨性关节炎的进展是胶原酶-3或基质金属蛋白酶-13。在MMPs中，MMP13是 最有效地降解II型胶原，主要的胶原蛋白存在于 关节软骨。基质金属蛋白酶-13在骨性关节炎软骨中表达， 类风湿滑膜，并在受到刺激的软骨细胞中诱导 炎性细胞因子白介素I与肿瘤坏死 α-因子(TNF)。因此，抑制基质金属蛋白酶-13在骨性关节炎和类风湿关节炎中具有重要意义。 软骨保护疗法的目标。我们发现了一种新奇的维甲酸， BMS-189453抑制胶原性关节炎小鼠基质金属蛋白酶-13的合成 模特。我们还证明了一种新的类固醇， 2-氰基-3，12-二氧杂环戊烯-1，9-二烯-28-酸(CDDO)也抑制基质金属蛋白酶-13 在软骨细胞中合成，并具有强大的抗炎特性。在这 应用，我们提出的研究将在细胞水平上定义 骨髓基质金属蛋白酶-13基因在骨髓基质金属蛋白酶-189453和环糊精抑制软骨细胞中的作用机制 具体地说，这些研究将定义转录因子和信号 转导中间体是这些化合物的靶标。因为类固醇 和维甲酸一起更有效地抑制胶原降解，我们将 测试BMS-189453和CDDO的组合，看看较低剂量的各自是否可以 被利用。我们将扩大这项工作，以确定软骨保护功效 BMS-189453和CDO单独和联合在短时间/长时间自发反应中的作用 小鼠骨性关节炎模型，以及在胶原性关节炎(CIA)小鼠模型中 拉。我们的目标是确定每种化合物在炎症中的效力 (CIA)和非炎症性(STR/ORT)关节炎模型，并评估 联合治疗的潜力，这可能导致较少的治疗 副作用。这项工作将研究细胞/分子事件和整个动物 一种新的类固醇和一种新型类固醇的软骨保护潜力的模型 治疗关节炎的新型维甲酸。

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.