Menarim Bruno C, MacLeod James N, Dahlgren Linda A
Gluck Equine Research Center, Department of Veterinary Science, College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY 40546, United States.
Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, United States.
World J Stem Cells. 2021 Jul 26;13(7):825-840. doi: 10.4252/wjsc.v13.i7.825.
Osteoarthritis (OA) is the most prevalent joint disease causing major disability and medical expenditures. Synovitis is a central feature of OA and is primarily driven by macrophages. Synovial macrophages not only drive inflammation but also its resolution, through a coordinated, simultaneous expression of pro- and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis. Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E and Nuclear factor-kappa B signaling pathways. However, such mechanisms are also innately required for mounting a pro-resolving response, and their blockage often results in chronic low-grade inflammation. Following minor injury, macrophages shield the damaged area and drive tissue repair. If the damage is more extensive, macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation. However, sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA. Recently, experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors, enhancing mechanisms of inflammation resolution, providing remarkable and long-lasting effects. Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors, macrophage progenitors also have a direct role in tissue repair. Macrophages constitute a large part of the early granulation tissue, and further transdifferentiate from myeloid into a mesenchymal phenotype. These cells, characterized as fibrocytes, are essential for repairing osteochondral defects. Ongoing "omics" studies focused on identifying key drivers of macrophage-mediated resolution of joint inflammation and those required for efficient osteochondral repair, have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties, not only OA.
骨关节炎（OA）是导致严重残疾和医疗支出的最常见关节疾病。滑膜炎是OA的核心特征，主要由巨噬细胞驱动。滑膜巨噬细胞不仅驱动炎症，还通过协调、同时表达促炎和抗炎机制来促进炎症的消退，这些机制对于对抗损伤和恢复体内平衡至关重要。目前的OA治疗主要基于抗炎原则，因此会阻断前列腺素E和核因子-κB信号通路等促炎机制。然而，这些机制对于引发促消退反应也是内在必需的，阻断它们往往会导致慢性低度炎症。轻微损伤后，巨噬细胞会保护受损区域并驱动组织修复。如果损伤更广泛，巨噬细胞会引发炎症，从骨髓中招募更多巨噬细胞，以最大限度地促进组织修复并最终消退炎症。然而，持续的损伤和炎症常常使滑膜巨噬细胞的促消退机制不堪重负，导致OA中观察到的慢性炎症和相关组织退变。最近，实验和临床研究表明，关节注射自体骨髓单个核细胞可使炎症关节补充巨噬细胞和造血祖细胞，增强炎症消退机制，产生显著且持久的效果。除了通过高浓度的白细胞介素-10和合成代谢生长因子创造一个促进消退的理想环境外，巨噬细胞祖细胞在组织修复中也有直接作用。巨噬细胞构成早期肉芽组织的很大一部分，并进一步从髓样转分化为间充质表型。这些细胞被称为纤维细胞，对于修复骨软骨缺损至关重要。正在进行的“组学”研究专注于确定巨噬细胞介导的关节炎症消退的关键驱动因素以及有效骨软骨修复所需的因素，有可能揭示开发工程化巨噬细胞或现成的促消退疗法的方法，这些疗法不仅能使OA患者受益，还能使患有多种关节炎的患者受益。
