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 E 2 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.

Intra-articular bone marrow mononuclear cell therapy improves lameness from naturally occurring equine osteoarthritis

“…A key topic that would be interesting to incorporate in future studies is how macrophage phenotypes change within OA joints before and after BMNC injection. Theoretically, the relatively naïve macrophage progenitors (BMNC) respond to the abnormal synovial environment in OA by developing a dynamic range of hybrid phenotypes and by providing necessary physiologic cues to trigger tissue repair by tilting the scales toward a homeostatic response ( 18 ). Unfortunately, macrophage polarization in vivo is much more complicated than was originally described by early in vitro studies using supraphysiological concentrations of lipopolysaccharide and cytokines in defined culture media ( 18 ).…”

“…Theoretically, the relatively naïve macrophage progenitors (BMNC) respond to the abnormal synovial environment in OA by developing a dynamic range of hybrid phenotypes and by providing necessary physiologic cues to trigger tissue repair by tilting the scales toward a homeostatic response ( 18 ). Unfortunately, macrophage polarization in vivo is much more complicated than was originally described by early in vitro studies using supraphysiological concentrations of lipopolysaccharide and cytokines in defined culture media ( 18 ). At present, our knowledge of targets to study macrophage phenotype in vivo and available reagents for equine-specific surface markers are insufficient to accurately design studies to inclusively evaluate the multifaceted immune response, including inflammation and its resolution.…”

“…Sham bone marrow aspirates were not performed on horses in the saline- or triamcinolone-treated groups, as lack of aspirate was not deemed to influence the outcome and was considered an invasive and therefore unnecessary procedure for client-owned horses. Bone marrow aspirates were collected from the 4th and 5th sternebrae (25 mL each site) using an 8-gauge Komiyashiki needle or 11-gauge Jamshidi needle and a heparinized 60 mL syringe (15,000 IU/aspirate) ( 18 , 41 , 57 , 58 ).…”

“…A full panel of 23 available cytokines and growth factors were screened using normal, OA and inflamed equine synovial fluid and those that were undetectable across these samples were eliminated from the multiplex. The selected cytokines and growth factors included in our study were based on prior publications and a knowledge of pathophysiology related to OA and BMNC ( 18 , 41 , 44 , 60 ). Prostaglandin E 2 was quantified by ELISA as previously described (R&D Systems, Minneapolis, MN, United States; SpectraMax M5 plate reader; Molecular Devices, San Jose, CA, United States) ( 44 ).…”

Downhill Running Increases Bone Mass Accumulation and Bone Tissues Morphology through the TGF-β/Smad Pathway in the Bone of Growing Mice

“…As the essential part of the human, bones have various functions, such as support, protection, endocrine, etc (1)(2). Its growth period is the second peak of bone growth and development, and it is also a sensitive period that affects the peak bone mass.…”