All these processes are activated through the p38 and ERK1/2 MAPK pathway (Scian et al., 2012). involved in bone resorption) by inducing an increase in osteoclastogenesis and osteoclast activation; therefore, increasing mineral and organic bone matrix resorption, contributing to bone damage. Given that the pathology induced by varieties involved joint cells, experiments carried out on synoviocytes exposed that besides inducing the activation of these cells to secrete chemokines, proinflammatory cytokines and MMPS, the infection also inhibits synoviocyte apoptosis. is an intracellular bacterium that replicates preferentially in the endoplasmic reticulum of macrophages. The analysis of and immune and osteoarticular cells may perform an important part in producing damage in joint and bone. illness are not fully understood. Bone damage can be attributed to the direct action of the bacteria or to an immunopathological process due to inflammation induced by innate immunity. No secreted proteases, toxins or lytic enzymes have been described so far in the bacteria; therefore, it is unlikely that this truth causes a direct deleterious effect, pointing out to innate GSK2636771 immune reactions as the major cause of osteoarticular pathology. Interplay Between Bone and Immune System The skeleton allows locomotion, calcium storage, and harboring hematopoietic stem cells from which blood and immune cells are derived. Although bone appears to be metabolically inert, it is actually a dynamic organ. Bone is composed of cells and an extracellular matrix which becomes mineralized from the deposition of calcium hydroxyapatite, which gives bone rigidity and strength. Bone offers three different cell types: osteoblasts -or bone-forming cells-, osteoclasts -or bone-resorbing cells, whose functions are intimately linked (Ikeda and Takeshita, 2016) and osteocytes, which are terminally differentiated osteoblasts inlayed within the mineralized bone matrix. Bone remodeling, a process coordinated between formation and degradation of bone handled by osteoblasts and osteoclasts, respectively, ensures bone homeostasis in healthy individuals. In order to balance bone formation and resorption, osteoblasts secrete RANKL that regulate the differentiation of osteoclasts, and osteocytes TGFA are the source of the Wnt antagonist sclerostin, and the Wnt signaling controlled by sclerostin regulate the activity of osteoblast (Karner et al., 2016), and osteocytes also secrete RANKL that regulate osteoclasts activity GSK2636771 (Chen et al., 2015). Several years of investigation possess highlighted the relationships between bone and immune cells as well as their overlapping regulatory mechanisms (El-Jawhari et al., 2016). For instance, osteoclasts originate from the same myeloid precursor cells that give rise to macrophages and myeloid dendritic cells. On the other hand, osteoblasts regulate hematopoietic stem cell niches from which blood and immune cells are derived. Moreover, many of the soluble mediators of immune cells, including cytokines and growth factors, regulate the activities of osteoblasts and osteoclasts. In physiological conditions, canonical osteoclast formation requires macrophage colony-stimulating element (M-CSF) and receptor activator element of nuclear element kB ligand (RANKL) (Lampiasi et al., 2016). These cytokines take action on cells of the monocyte-macrophage lineage, inducing their fusion to form multinucleated active resorbing cells. In the bone milieu, M-CSF is usually produced by osteoblasts and bone marrow stromal cells. It induces proliferation of osteoclast precursors, and differentiation and survival of mature osteoclasts (Fuller et al., 1993; Tanaka et al., 1993). M-CSF induces RANKL receptor expression, RANK, on mononuclear osteoclast precursors which then interacts with membrane-bound RANKL on surrounding osteoblasts and stromal cells to initiate osteoclasts differentiation (Yasuda et al., 1998). RANKL is present as both a transmembrane molecule and a secreted form. Its conversation with RANK is usually opposed by osteoprotegerin (OPG), a neutralizing soluble decoy receptor produced by marrow stromal cells and osteoblasts (Grundt et al., 2009). In addition to M-CSF and RANKL, a number of other cytokines and growth factors are known to substitute these two molecules and induce a non-canonical osteoclast formation (Lampiasi et al., 2016). Bone-marrow-derived and circulating osteoclast precursors are capable of differentiating into osteoclasts in the presence GSK2636771 of M-CSF and substitutes for RANKL such as TNF-, LIGHT (a receptor expressed in T lymphocytes), APRIL (a proliferation inducing ligand), BAFF (a B cell activating factor), the nerve growth factor, insulin-like growth factor (IGF)-I and II, TGF-, IL-6, IL-11, IL-8; or in the presence of RANKL and substitutes for M-CSF such as a vascular endothelial growth factor, placental growth factor, FLt-3 ligand and hepatocyte growth factor (Lampiasi et al., 2016). Interestingly, IL-1, IL-7, IL-17, and IL- 23 have also been involved in non-canonical osteoclastogenesis (Mori et al., 2013), mostly by inducing indirectly osteoclastogenesis and promoting RANKL release from other cells (Ikeda and Takeshita, 2016) and RANK on osteoclast precursors (Adamopoulos et al., 2010). However, it has been exhibited that Th17 cells produce RANKL by themselves (Adamopoulos et al., 2010). IL-17 also enhances local inflammation and increases the production of inflammatory cytokines which further promote RANKL expression and.
