The Role of MIF in Osteoarthritis

描述(申请人提供)：这个探索性和发展性(R21)项目的目标是确定巨噬细胞移动抑制因子(MIF)在小鼠骨关节炎(OA)发展中的作用，并获得有关MIF在人类关节组织中功能的数据。这一建议得到了一项令人兴奋的初步研究的支持，在该研究中，我们发现12个月大的MIF基因敲除小鼠比年龄和品系匹配的对照组发生的自发性骨性关节炎要少得多，这意味着MIF是参与年龄相关性骨性关节炎发展的关键细胞因子。MIF最初被发现是由T细胞产生的一种抑制巨噬细胞迁移的因子，后来发现许多类型的细胞都会产生MIF，包括巨噬细胞和滑膜成纤维细胞。MIF在调节先天和获得性免疫反应中发挥作用，并与许多急性和慢性炎症有关，包括脓毒症、动脉粥样硬化和类风湿性关节炎。重要的是，这个建议的新颖性是，MIF在OA发病机制中的作用从未被研究过。在目标1中，我们建议确定MIF的缺失是否降低了小鼠自发的年龄相关的骨关节炎和损伤诱导的骨关节炎的严重程度。我们假设，与年龄和应变相匹配的对照组相比，MIF-/-小鼠的损伤诱导和年龄相关的骨性关节炎将较少。对MIF-/-小鼠的研究将得到使用抑制MIF活性的单抗的野生型小鼠研究的补充。在目标2中，我们将确定MIF激活关节组织细胞分解代谢途径的机制。我们假设MIF将通过其受体CD74从滑膜成纤维细胞、软骨细胞和半月板细胞中释放出来，并通过其受体CD74以自分泌和旁分泌的方式促进分解代谢介质的产生。这一目标的实验将包括测量CD74-/-小鼠年龄相关性骨性关节炎的严重程度。目前，尚无治疗方法可以延缓骨性关节炎的进展。由于已经产生了抗体和小分子抑制剂来抑制MIF，我们的工作结果将用于支持对MIF在OA中的进一步研究，并可能迅速转化为一种新的治疗方法。在AIM 2中，MIF在关节组织破坏中作用的相关机制的阐明也将与RA相关，在RA中，类似的分解代谢 路径是活跃的。

DESCRIPTION (provided by applicant): The objective of this exploratory and developmental (R21) project is to determine the role of macrophage migration inhibitory factor (MIF) in the development of osteoarthritis (OA) in mice and obtain data on MIF function in human joint tissues. The proposal is supported by an exciting preliminary study in which we discovered that 12 month-old MIF knock-out mice develop significantly less spontaneous OA than age and strain-matched controls, implicating MIF as a key cytokine involved in the development of age-associated OA. Originally discovered as a factor produced by T cells that inhibited macrophage migration, MIF was subsequently found to be produced by many cell types, including macrophages and synovial fibroblasts. MIF has been noted to function in the regulation of innate and adaptive immune responses and has been implicated in a number of acute and chronic inflammatory conditions including sepsis, atherosclerosis, and rheumatoid arthritis. Important to the novelty of this proposal, a role for MIF in the pathogenesis of OA has never been studied. In aim 1, we propose to determine if deletion of MIF reduces the severity of spontaneous age-related OA and injury-induced OA in mice. We hypothesize that MIF-/- mice will have less injury-induced and age-related OA compared to age- and strain-matched controls. Studies on MIF-/- mice will be complemented by studies in wild type mice using a monoclonal antibody that inhibits MIF activity. In aim 2, we will determine the mechanism for MIF activation of catabolic pathways in joint tissue cells. We hypothesize that MIF will be released from synovial fibroblasts, chondrocytes, and meniscal cells in response to catabolic stimuli and act in an autocrine and paracrine manner via its receptor, CD74, to promote the production of catabolic mediators. Experiments in this aim will include measuring the severity of age-associated OA in CD74-/- mice. Currently, no treatment exists which can slow the progression of OA. Because antibodies and small molecule inhibitors have already been produced to inhibit MIF, the results of our work would be used to support further studies on MIF in OA and could be rapidly translated into a novel therapeutic approach. The elucidation of mechanisms relevant to MIF's role in joint tissue destruction in aim 2 will also be relevant to RA where similar catabolic pathways are active.