Physiological/pathological differentiation of the mononuclear phagocyte system in rheumatoid arthritis (RA). (a) Physiological differentiation of the mononuclear phagocyte system (MPS) (steady-state cytokine and growth factor milieu). In the human MPS, monocytes (M) differentiate from a CD34+ stem cell via an intermediate step of monoblasts. Monocytes leave the bone marrow and remain in circulation for approximately 3 days. Upon entering various tissues, they differentiate into different types of resident macrophages (Mφ), including synovial macrophages. It is believed that these mature cells do not recirculate, surviving for several months in their respective tissues until they senesce and die. Some circulating monocytes retain the potential for differentiating into dendritic cells and osteoclasts (asterisk in the insert). The steady-state myeloid differentiation involves many factors, including granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α), which are produced by resident bone marrow macrophages (reviewed in ). (b) Increased plasticity of myeloid differentiation and its possible role in RA (augmented cytokine and growth factor milieu). Human bone marrow intermediate cells can differentiate into macrophages or dendritic cells in the presence of c-kit ligand, GM-CSF, and TNF-α. TNF-α, in turn, inhibits the differentiation of monocytes into macrophages in vitro and, together with GM-CSF, directs the differentiation of precursor cells into dendritic cells, another important arm of the accessory cell system. Also, either IL-11 or vitamin D3 and dexamethasone induce the differentiation of bone marrow cells or mature macrophages into osteoclasts, cells involved in the destruction of subchondral bone in RA. Osteoclasts and dendritic cells can also be derived from circulating monocytes upon stimulation with macrophage colony-stimulating factor (M-CSF) or IL-4 plus GM-CSF. This plasticity, and its dependence on growth factors or cytokines that are clearly elevated in peripheral blood and bone marrow of patients with RA, may explain some differentiation anomalies in the disease and also the efficacy of some anti-rheumatic drugs. Non-specific enhancement of monocyte maturation and tissue egression, in turn, are consistent with the known alterations in inflammation (reviewed in ). The differentiation paths potentially relevant to RA are indicated by bold arrows. The jagged arrows represent possible sites of cell activation. CFU-GM, colony-forming units-granulocyte macrophage; CFU-M, colony-forming units-macrophage; MNC, mononuclear cells; PM(N), polymorphonuclear leukocytes. Reproduced with permission from Kinne RW, Stuhlmuller B, Palombo-Kinne E, Burmester GR: The role of macrophages in rheumatoid arthritis. In Rheumatoid Arthritis. Edited by Firestein GS, Panayi GS, Wollheim FA. New York: Oxford University Press; 2006:55–75 .