GM-CSF was originally defined as a hemopoietic growth factor [93]. However, it is able to act on mature myeloid cells and has other functions, acting as a pro-inflammatory cytokine [94]. GM-CSF influences dendritic cells and macrophage recruitment into inflammatory sites [95]. GM-CSF is also important for effective antigen processing and presenting function in antigen present cells (APC) [96]. Recent studies have highlighted a surprising role for GM-CSF responsive monocyte-derived dendritic

cells in the pathogenicity of Th17 cells, which are important mediators for inflammatory diseases [97]. Moreover, IL-17 produced by activated Th17 induced the GM-CSF production ABT-199 concentration from macrophages [98]. GM-CSF is produced by a wide variety of cell types, including activated T-cells, B-cells, macrophages, endothelial cells and fibroblasts, and its production is increased by inflammatory factors such as IL-1, TNF and PGE2. GM-CSF is detected abundantly in RA synovial fluid and is scarcely detected in non-inflammatory synovial fluid [99]. GM-CSF was also detected in synovial fluids from patients with ID and/or OA of TMJ, but was not detected in normal

controls [100]. GM-CSF was detected in the erosive inflammatory reaction around orthopedic implants [101] and in osteolytic bone metastasis from malignant tumors [102]. However, studies examining the effects of GM-CSF on osteoclastogenesis have reported contradictory results. It has been reported that GM-CSF induced the fusion of prefusion osteoclasts to form multinucleated osteoclasts, making the osteoclast capable of bone resorption [103]. In contrast, another study demonstrated that check details GM-CSF abolished monocytic differentiation into osteoclasts while inducing DC differentiation even in the presence of M-CSF and RANK ligand [104]. Although the basis for these apparently contradictory results reached by these different approaches is unclear, this uncertainty as to the effects of GM-CSF Dehydratase on osteoclast differentiation may be related to the stages for osteoclast differentiation and/or the potential

significance of its increased production at sites of inflammation. B-cell lymphoma 2-related protein A1 (BCL2A1), also known as Bcl-2-related gene expressed in fetal liver (Bfl-1), is among the top 10 up-regulated genes in FLS with inflammatory stimulation, ranked 9 with IL-1β-stimulation and ranked 7 with TNF-α-stimulation (Table 1). BCl2A1 is a member of the B-cell lymphoma 2 (BCL2) protein family, which are important cell death regulators [105]. The BCL2 family comprises both pro- and anti-apoptotic proteins [106]. BCL2A1 is an anti-apoptosis protein of the BCL2 family whose main function is binding to pro-apoptosis BCL2 members such as BAK, and then inhibiting BAK function [106] and [107]. Pro-apoptosis proteins induce the release of cytochrome c from mitochondria, caspase activation and apoptosis [106] and [107].