Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups

Abstract

Cellular associations in the bone microenvironment are involved in modulating the balance between bone remodeling and resorption, which is necessary for maintaining a normal bone morphology. Macrophages and osteoclasts are both vital components of the bone marrow. Macrophages can interact with osteoclasts and regulate bone metabolism by secreting a variety of cytokines, which make a significant contribution to the associations. Although, recent studies have fully explored either macrophages or osteoclasts, indicating the significance of these two types of cells. However, it is of high importance to report the latest discoveries on the relationships between these two myeloid-derived cells in the field of osteoimmunology. Therefore, this paper reviews this topic from three novel aspects of the origin, polarization, and subgroups based on the previous work, to provide a reference for future research and treatment of bone-related diseases.

Keywords: associations; cytokines; macrophages; origin; osteoclasts; polarization; subgroups.

Figure 1

The monocyte/macrophage origin of osteoclasts. Hematopoietic stem cells myeloid colony-forming units (M-CFU) from bone marrow or yolk sac is the main site of myeloid cell production. Recent researches have shown that tissue-resident macrophages initially arise from myeloid stem cells (M-CFU) in the yolk sac of the developing embryo. In M-CFU, early expression of PU.1 and Mitf induces the emergence of M-CSFR (the receptor for M-CSF). Subsequently, in combination with macrophage colony‐stimulating factor (M-CSF) and receptor activator of NF‐κB ligand (RANKL), M-CFU can differentiate directly into osteoclasts. But in the separate action of M-CSF, M-CFU can differentiate into M-CSF-dependent macrophage and dendritic cell progenitor (MDP). MDP can differentiate into both dendritic cells and monocytes, the latter of which can differentiate into pro-monocytes under the sustained action of M-CSF. Pro-monocytes can differentiate to form specifically marked monocytes, namely: LY6C⁺ or LY6C^- blood monocytes, under appropriate stimulation, such as M-CSF, TNF. Monocytes (Ly-6C⁻) induced by M-CSF develop into macrophages, but the addition of RANKL converts monocytes into osteoblasts commitment. Early-stage Ly-6C⁺ monocytes exhibit a high potential for osteoclast commitment in response to M-CSF and RANKL activation while still retaining the capacity to transform into Ly6C^-monocytes. Completely differentiated macrophages induced by M-CSF and RANKL can fuse to become osteoclasts. Under pathological situations, macrophages can generate multinucleated giant cells (MGCs) when stimulated with M-CSF or stimulating factor (GM-CSF) and interleukins (IL-4, IL-13). MGCs continue to differentiate into osteoblasts in the presence of common fusion mediators. In addition, immature dendritic cells have the potential for osteolytic differentiation.

Figure 2

Macrophage polarization and osteoclasts. 1. Circulating macrophages change their phenotype according to the external environment. In the presence of cytokines, such as interferon (IFN), reactive oxygen species (ROS), interleukin-12 (IL-12), and tumor necrosis factor (TNF), macrophages polarize to M1 type. In response to interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), and other cytokines, macrophages can be polarized to M2 type. 2. Macrophages can produce cytokines with opposite effects in different polarization states. M1 macrophages can secrete cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), etc., which generally show the effect of activating osteoclasts and promoting bone resorption. M2 macrophages can secrete cytokines, such as IL-10, bone morphogenetic protein-2 (BMP-2), transforming growth factor-β1(TGF-β1), etc., most of which can inhibit osteoclastic bone resorption.