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）：该探索性和开发性（R21）项目的目标是确定巨噬细胞迁移抑制因子（MIF）在小鼠骨关节炎（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 敲除小鼠发生的自发性 OA 明显低于年龄和品系匹配的对照组，这表明 MIF 是参与与年龄相关的 OA 发生的关键细胞因子。 MIF 最初被发现是由 T 细胞产生的抑制巨噬细胞迁移的因子，随后发现 MIF 由许多细胞类型产生，包括巨噬细胞和滑膜成纤维细胞。 MIF 已被发现在调节先天性和适应性免疫反应中发挥作用，并与许多急性和慢性炎症性疾病有关，包括败血症、动脉粥样硬化和类风湿性关节炎。对于该提案的新颖性而言，重要的是 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 的缺失是否会降低小鼠自发性年龄相关 OA 和损伤诱导 OA 的严重程度。我们假设，与年龄和品系匹配的对照组相比，MIF-/- 小鼠的损伤引起的和与年龄相关的 OA 较少。使用抑制 MIF 活性的单克隆抗体对野生型小鼠进行的研究将补充对 MIF-/- 小鼠的研究。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。我们假设滑膜成纤维细胞、软骨细胞和半月板细胞响应分解代谢刺激而释放 MIF，并通过其受体 CD74 以自分泌和旁分泌方式发挥作用，促进分解代谢介质的产生。此目的的实验将包括测量 CD74-/- 小鼠中与年龄相关的 OA 的严重程度。目前，尚无可以减缓 OA 进展的治疗方法。由于已经生产出抑制 MIF 的抗体和小分子抑制剂，因此我们的工作结果将用于支持对 OA 中 MIF 的进一步研究，并可以快速转化为一种新的治疗方法。目标 2 中与 MIF 在关节组织破坏中的作用相关的机制的阐明也将与 RA 相关，其中类似的分解代谢 路径是活跃的。