OSM Pathway
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OSM Pathway

Proinflammatory cytokines are the principal intercellular mediators of the tissue reaction to trauma and infection. Members of IL-6 (Interleukin-6) hematopoietic cytokine family, that include IL-6, IL-11, LIF (Leukemia Inhibitor Factor), OSM (Oncostatin M), CNF (Ciliary Neurotrophic Factor), Cardiotrophin-1, and the recently described novel Neurotrophin-1/B-Cell Stimulatory Factor-3 play a particularly prominent role in orchestrating initiation and progression of inflammation, hematopoiesis, acute phase response, bone and heart development as well as neurogenesis. Their redundant effect is attributed to the shared use of the common signal transducing receptor chain GP130 (Glycoprotein-130). GP130 is homodimerized by IL-6 and IL-11 upon binding to their ligand-specific Alpha-receptors. The other cytokines of this family trigger the heterodimerization of GP130 with the LIFR (LIF Receptor) or the OSMR (OSM-specific Receptor). Human OSM has the capability to signal both via GP130-LIFR and GP130-OSMR heterodimers to form the high affinity, signaling-competent OSMRI or OSMRII (Ref.1).

OSM is produced by activated monocytes and lymphocytes (e.g. at sites of inflammation) and acts locally on stromal cells. Stromal cells in turn respond prominently by enhanced production of IL-6 and LIF. IL-6 and LIF enter into circulation and participate in the recruitment of systemic inflammatory response that includes the acute phase reaction of the liver (Ref.2). In bovine and human endothelial cells, OSM promotes the expression of urokinase plasminogen activator, basic FGF (Fibroblast Growth Factor), GCSF (Granulocyte Colony-Stimulating Factor), and GMCSF (Granulocyte-Macrophage Colony Stimulating Factor). In human fibroblasts, OSM modulates not only matrix metalloproteinases but also TIMP (Tissue Inhibitor of Metalloproteinase) (Ref.3). OSM binds to a receptor shared with LIFR-Beta (LIF-Receptor-Beta) and GP130, and to a high affinity OSMR-Beta (OSM-specific Receptor-Beta) that binds only OSM and also involves the subunit GP130. The two receptors for OSM may be functionally different and they can be coupled to different signal transduction pathways. Ligand-induced oligomerization of receptor subunits activates JAKs (Janus protein-tyrosine kinases, JAK1, JAK2 and TYK2 kinases), which in turn phosphorylate tyrosine residues in the receptor cytoplasmic domain. This phosphorylated tyrosine create docking sites for STAT1, STAT3, and STAT5 (Signal Transducer And Activator of Transcription), protein-tyrosine phosphatase SHP2, and linker proteins such as GAB1 (GRB2-Associated Binding protein-1), GRB2 (Growth Factor Receptor-Bound protein 2)-SOS, or SHC, which propagate the signal to other pathways such as MEK (MAPK/ERK Kinases), ERK1/2 (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase) and PI3K (Phosphatidylinositol-3 Kinase)). Receptor signaling is manifested by the activation of genes such as acute phase proteins or CDK (Cyclin-Dependent Kinase) inhibitor p21/WAF1 (Wild type p53-Activated Fragment-1), which is primarily activated through STATs and immediate early response genes such as c-Fos and c-Jun, primarily through ERK1/2 (Ref.4). OSMR-Beta does not possess a phosphorylation site for ERK1/2 and, thus, do not appear to be appreciably influenced by activated ERK.

As a pleiotrophic cytokine, OSM elicits many different biological functions in different cell types, among which its ability to regulate cell growth and differentiation is most notable. OSM is involved in various systemic and local responses, such as regulation of the acute phase reaction, hematopoiesis, bone remodeling, and homeostasis of the ECM (Extracellular Matrix), and can act as a mediator for both the proliferation and the growth arrest of various cell lines (Ref.5). It stimulates the growth of normal fibroblasts, normal rabbit VSMC (Vascular Smooth Muscle Cells), myeloma cells, and AIDS-related Kaposi’s sarcoma cells. OSM inhibits the growth of many cancer cell types, including human melanoma, neuroblastoma, fibro sarcoma, rhabdomyosarcoma, ovarian, lung, stomach and breast carcinoma cell lines. The inhibitory or stimulatory effects of OSM on cell growth depend on target cell type (Ref.6). Due to its ability to induce TIMP1 and TIMP3, profibrotic properties have been attributed to this cytokine. In addition, OSM plays a role in the wound healing process and in attenuation of the inflammatory response. Compared with other IL-6-type cytokines, OSM often induces stronger effects with regard to STAT and MAPK (Mitogen-Activated Protein Kinase) activation, induction of protease inhibitors or growth inhibition (Ref.1). In rheumatoid arthritis, OSM levels correlate with disease severity, whereas in atherosclerosis, OSM and TNF-Alpha (Tumor Necrosis Factor-Alpha) colocalize in atherosclerotic plaques. OSM is also elevated in some forms of hepatic cirrhosis, systemic sclerosis and endotoxin-induced renal disease (Ref.7).