Bone marrow mononuclear cells for joint therapy: The role of macrophages in inflammation resolution and tissue repair

Abstract

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 E₂ 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.

Keywords: Osteoarthritis; Arthropathy; Synovitis; Hematopoietic progenitor; Homeostasis; Cell therapy

Core Tip: Synovial macrophages are essential for joint integrity. Following injury, macrophages incite inflammation recruiting more macrophages from the bone marrow to counteract damage and promote tissue repair. Synovial macrophages are further essential to resolve inflammation recovering joint homeostasis. However, sustained damage frequently overwhelms pro-resolving functions of synovial macrophages, leading to chronic inflammation and degeneration. This review summarizes the dual role of macrophages in the maintenance of joint homeostasis and the emergent therapeutic use of macrophage progenitors isolated from the bone marrow to promote endogenous resolution of joint inflammation and recovery of homeostasis, while preserving physiological mechanisms negatively affected by anti-inflammatories.