Modulation of osteoclast formation and function to prevent joint destruction in rheumatoid arthritis

风湿性关节炎是一种影响大约20万澳大利亚人的疾病。它的特点是痛苦的关节破坏导致工作残疾、生活质量下降和预期寿命减少。关节炎的常规治疗方法可以减少炎症，但不能依靠它来控制骨骼和关节的破坏。尽管关节疼痛和肿胀有短期和中期的改善，但患者的关节功能往往长期恶化。这一悖论的一个原因可能是，尽管研究主要集中在炎症上，但对导致骨骼损伤的过程知之甚少。正常情况下，被称为破骨细胞的特殊骨细胞在骨骼的生长和维护过程中进行骨骼分解。在类风湿性关节炎中，这些细胞是关节损伤的罪魁祸首；因此，这项建议将重点放在抑制这些细胞的活性上，作为一种新的治疗方法。到目前为止，我们使用人类类风湿性关节炎模型的工作已经证明，通过使用一种名为骨保护素的抑制剂选择性地靶向破骨细胞，可以将关节炎症与关节损伤分开。除了骨保护素，我们还鉴定了两个新的分子OCIL和SFRP-1，并表明它们存在于患有关节炎的动物和人类的关节中。我们实验室最近的实验表明，在试管中，OCIL和SFRP-1(类似骨保护素)可以阻断破骨细胞的活性。SFRP-1分子还可能阻断关节炎中一种非常重要的信使分子，即肿瘤坏死因子。因此，我们建议研究OCIL和SFRP-1在关节炎小鼠关节中的作用。我们预计这些新的抑制剂将对关节损伤起到良好的作用。如果是这样的话，它们可能会接受进一步的人体测试。我们相信，沿着这些思路进行的研究可能会为一种全新的治疗方法提供理论基础，以改善关节炎患者的长期结果。

Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may be that while research has mainly focused on inflammation, far less is known about the processes responsible for bone damage. Normally, specialised bone cells called osteoclasts carry out bone breakdown during growth and maintenance of the skeleton. In rheumatoid arthritis, these cells are responsible for the joint damage; this proposal, therefore, focuses on inhibiting the activity of these cells as a new therapy. So far, our work using a model of human rheumatoid arthritis has demonstrated that it is possible to separate joint inflammation from joint damage by selectively targeting osteoclasts with an inhibitor known as Osteoprotegerin. Besides Osteoprotegerin, we have identified two novel molecules named OCIL and sFRP-1 and shown that they are present in the joints of animals and humans with arthritis. Very recent experiments in our laboratory show that in the test tube, OCIL and sFRP-1 (like Osteoprotegerin) block osteoclast activity. The sFRP-1 molecule may also block a very important messenger molecule in arthritis called tumour necrosis factor. We therefore propose to study the effect of OCIL and sFRP-1 in the joints of mice with arthritis. We expect that these new inhibitors will have favorable effects on joint damage. If so, they could undergo further testing for use in humans. We believe that investigations along these lines may provide a rationale for an entirely new treatment approach to improve the long term outcome for patients with arthritis.