The Role of MIF in Osteoarthritis

MIF 在骨关节炎中的作用

• 批准号: 8839493
• 负责人: RICHARD F LOESER
• 金额: $ 20.27万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839493
• 关键词: Acute; Age; Animals; Antibodies; Atherosclerosis; CXCR4 gene; Cartilage; Cell Surface Receptors; Cells; Chondrocytes; Chronic; Complement; Complex; Cultured Cells; Data; Degenerative polyarthritis; Development; Disease Progression; Elderly; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Health; Human; IL8RB gene; Immigration; Immune response; Immunohistochemistry; In Vitro; Inflammatory; Injury; Joints; Knee; Knee joint; Knockout Mice; Ligands; Matrix Metalloproteinases; Measures; Medial meniscus structure; Mediator of activation protein; Meniscus structure of joint; Migration Inhibitory Factor; Mitogen-Activated Protein Kinases; Modeling; Monoclonal Antibodies; Mus; Normal tissue morphology; Pathogenesis; Pathway interactions; Play; Process; Production; Regulation; Rheumatoid Arthritis; Role; Sepsis; Severities; Signal Transduction; Stimulus; Synovial Membrane; T-Lymphocyte; TLR4 gene; TNF gene; Tissue Donors; Tissues; Toll-Like Receptor 1; Translating; Wild Type Mouse; Work; age related; autocrine; bone; cell type; cytokine; disability; fibroblast migration inhibitory factor; human tissue; in vivo; inhibitor/antagonist; macrophage; migration; monocyte; neutralizing antibody; novel therapeutic intervention; paracrine; phenylpyruvate tautomerase; protein degradation; receptor; research study; response; small molecule

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.

描述（由申请人提供）：该探索性和发育（R21）项目的目的是确定巨噬细胞迁移抑制因子（MIF）在小鼠中骨关节炎（OA）发展中的作用，并获得有关人类关节组织中MIF功能的数据。该提案得到了一项令人兴奋的初步研究的支持，我们发现12个月大的MIF敲除小鼠的自发OA的发展明显低于年龄和菌株匹配的对照，这意味着MIF是与年龄相关的OA发展有关的关键细胞因子。最初被发现是由T细胞抑制巨噬细胞迁移的T细胞产生的因素，随后被发现是由许多细胞类型（包括巨噬细胞和滑膜成纤维细胞）产生的。已经注意到MIF在调节先天和适应性免疫反应的调节中起作用，并与许多急性和慢性炎症疾病有关，包括败血症，动脉粥样硬化和类风湿关节炎。对于该提案的新颖性至关重要，MIF在OA发病机理中的作用从未被研究。在AIM 1中，我们建议确定MIF缺失是否会降低小鼠自发年龄相关的OA和损伤诱导的OA的严重程度。我们假设MIF - / - 小鼠与年龄和应变匹配的对照相比，损伤引起的OA的损伤诱导和年龄有关。使用抑制MIF活性的单克隆抗体对MIF - / - 小鼠的研究将得到野生型小鼠的研究。在AIM 2中，我们将确定关节组织细胞中MIF激活分解代谢途径的机制。我们假设MIF将从滑膜成纤维细胞，软骨细胞和半月板细胞中释放出对分解代谢刺激的响应，并通过其受体CD74以自分泌和旁分泌方式作用，以促进分解代谢介体的产生。此目标的实验将包括测量CD74 - / - 小鼠中与年龄相关的OA的严重性。目前，尚无治疗可以减缓OA的进展。由于已经产生了抗体和小分子抑制剂来抑制MIF，因此我们的工作结果将用于支持OA中MIF的进一步研究，并可以迅速转化为一种新型的治疗方法。阐明与MIF在AIM 2中的关节组织破坏中作用相关的机制也将与RA有关，而RA则相似 途径是活动的。