Ghosh P
Department of Surgery, University of Sydney, The Institute of Bone and Joint Research, Royal North Shore Hospital of Sydney, St Leonards, NSW, Australia.
Semin Arthritis Rheum. 1999 Feb;28(4):211-67. doi: 10.1016/s0049-0172(99)80021-3.
Structure-modifying osteoarthritis (OA) drugs (SMOADs) may be defined as agents that reverse, retard, or stabilize the underlying pathology of OA, thereby providing symptomatic relief in the long-term. The objective of this review was to evaluate the literature on sodium pentosan polysulfate (NaPPS) and calcium pentosan polysulfate (CaPPS), with respect to the pathobiology of OA to ascertain whether these agents should be classified as SMOADs.
Published studies on NaPPS and CaPPS were selected on the basis of their relevance to the known pathobiology of OA, which also was reviewed.
Both NaPPS and CaPPS exhibit a wide range of pharmacological activities. Of significance was the ability of these agents to support chondrocyte anabolic activities and attenuate catabolic events responsible for loss of components of the cartilage extracellular matrix in OA joints. Although some of the anti-catabolic activities may be mediated through direct enzyme inhibition, NaPPS and CaPPS also have been shown to enter chondrocytes and bind to promoter proteins and alter gene expression of matrix metalloproteinases and possibly other mediators. In rat models of arthritis, NaPPS and CaPPS reduced joint swelling and inflammatory mediator levels in pouch fluids. Moreover, synoviocyte biosynthesis of high-molecular-weight hyaluronan, which is diminished in OA, was normalized when these cells were incubated with NaPPS and CaPPS or after intraarticular injection of NaPPS into arthritic joints. In rabbit, canine, and ovine models of OA, NaPPS and CaPPS preserved cartilage integrity, proteoglycan synthesis, and reduced matrix metalloproteinase activity. NaPPS and CaPPS stimulated the release of tissue plasminogen activator (t-PA), superoxide dismutase, and lipases from vascular endothelium while concomitantly decreasing plasma levels of the endogenous plasminogen activator inhibitor PAI-1. The net thrombolytic and lipolytic effects exhibited by NaPPS and CaPPS may serve to improve blood flow through subchondral capillaries of OA joints and improve bone cell nutrition. In geriatric OA dogs, NaPPS and CaPPS reduced symptoms, as well as normalized their thrombolytic status, threshold for platelet activation, and plasma triglyceride levels. These hematologic parameters were shown to be abnormal in OA animals before drug treatment. Similar outcomes were observed in OA patients when CaPPS or NaPPS were given orally or parenterally in both open and double-blind trials.
The data presented in this review support the contention that NaPPS and CaPPS should be classified as SMOADs. However, additional long-term clinical studies employing methods of assessing joint structural changes will be needed to confirm this view.
结构修饰性骨关节炎（OA）药物（SMOADs）可定义为能够逆转、延缓或稳定OA潜在病理过程，从而长期缓解症状的药物。本综述的目的是评估关于戊聚糖多硫酸酯钠（NaPPS）和戊聚糖多硫酸钙（CaPPS）的文献，涉及OA的病理生物学，以确定这些药物是否应归类为SMOADs。
根据与已知OA病理生物学的相关性，挑选已发表的关于NaPPS和CaPPS的研究，同时对OA病理生物学也进行了综述。
NaPPS和CaPPS均具有广泛的药理活性。这些药物能够支持软骨细胞的合成代谢活动，并减轻导致OA关节软骨细胞外基质成分丢失的分解代谢事件，这一点具有重要意义。尽管某些抗分解代谢活性可能是通过直接抑制酶介导的，但NaPPS和CaPPS也已被证明可进入软骨细胞并与启动子蛋白结合，改变基质金属蛋白酶以及可能其他介质的基因表达。在大鼠关节炎模型中，NaPPS和CaPPS可减轻关节肿胀并降低腹腔液中炎症介质水平。此外，当这些细胞与NaPPS和CaPPS孵育或向关节炎关节内注射NaPPS后，OA中减少的滑膜细胞高分子量透明质酸生物合成恢复正常。在兔、犬和羊的OA模型中，NaPPS和CaPPS可保持软骨完整性、蛋白聚糖合成，并降低基质金属蛋白酶活性。NaPPS和CaPPS可刺激血管内皮释放组织纤溶酶原激活物（t-PA）、超氧化物歧化酶和脂肪酶，同时降低内源性纤溶酶原激活物抑制剂PAI-1的血浆水平。NaPPS和CaPPS表现出的净溶栓和脂解作用可能有助于改善OA关节软骨下毛细血管的血流并改善骨细胞营养。在老年OA犬中，NaPPS和CaPPS可减轻症状，并使它们的溶栓状态、血小板激活阈值和血浆甘油三酯水平恢复正常。在药物治疗前，这些血液学参数在OA动物中显示异常。在开放和双盲试验中，当口服或胃肠外给予CaPPS或NaPPS时，OA患者也观察到了类似结果。
本综述所呈现的数据支持将NaPPS和CaPPS归类为SMOADs的观点。然而，需要采用评估关节结构变化方法的更多长期临床研究来证实这一观点。
