Oncostatin M receptor

Expression

OSMR is widely expressed across non-haematopoietic, hepatocytes, mesothelial cells, glial cells and epithelial cell types across various organs and mammary glands. OSM receptor is abundantly expressed on endothelial and stromal/fibroblast cells in the lung of mice.=

In vitro expression of OSMR  in fetal hepatocytes is upregulated by OSM stimulation.

OSMR expression has been shown to be induced by parathyroid hormone in osteoblasts and OSM.

Signaling

Intracellular cell signalling occurs as a consequence of extracellular binding of the ligand OSM to OSMR complexes, formed from dimerization with receptor subunits such as gp130. Activation of the OSMR-gp130 complex by OSM triggers Janus Kinase 1 (JAK1) and Jak2 cross phosphorylation of tyrosine residues on the intracellular receptor domain. Downstream signaling activation of the OSMR-gp130 complex  along the JAK1 pathway leads to IL-6 signalling which is linked with activation of the MAPK cascade, PI3K cascade and STAT3 activation.

OSM induced recruitment of SHC to the OSMRβ sub-unit has been shown to enhance Ras/Raf/MAPK signaling and lead p38 and JNK activation.

Clinical significance

The oncostatin M receptor is associated with primary cutaneous amyloidosis.

OSM signaling via the OSMR is believed to play an important role in bone turnover as Mice lacking the OSMR receptor have osteopetrotic phenotypes. Lack of OSMRβ activity has also been linked to adipose tissue inflammation and insulin resistance preceding obesity.

OSM in-vivo regulation of hematopoiesis, through stimulation of stromal cells & hematopoietic progenitors - megakaryocytic and erythrocytic progenitors, is carried out by the OSMRβ receptor.

Heart Disease

Inhibition of the OSMRβ extracellular subunit has been shown has been shown to prevent OSM-mediated down-regulation of myoglobin in cardiomyocytes and related apoptosis of cardiomyocytes in inflammatory heart failure.

OSMRβ is not only overexpressed in patients with chronic dilated cardiomyopathy but has been shown to control dedifferentiation and loss of sarcomeric structures in myocardial infarction and dilated cardio myopathy. OSM and OSMRβ mediated dedifferentiation  has been shown to increase chances of survival after acute myocardial damage but poor survival rates and compromised pump functions in chronic disease states.

Cancer

OSMR activates STAT3 and transforming growth factor β (TGF-β) effector SMAD3 to regulate expression of genes responsible for inducing a mesenchymal/CSC phenotype.

OSM-induced biological effects on breast tumor– derived cell lines were specifically mediated through the gp130/OSMRB complex.

the OSM receptor (OSMR) is overexpressed in cervical squamous cell carcinomas and, independent of tumor stage, is associated with adverse clinical outcomes and higher relative risk of death.

OSM and OSMRβ are co-expressed and lead to STAT 3 activation malignant human ovarian epithelial cells.

The OSMR β  promoter gene is highly methylated in primary Colorectal Cancer tissues and  fecal DNA, it is a highly specific diagnostic biomarker of Colorectal Cancer.

References

References

1. (December 1996). "Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation". The Journal of Biological Chemistry.
2. "Entrez Gene: oncostatin M receptor".
3. (September 2018). "The oncostatin M-stromal cell axis in health and disease". Scandinavian Journal of Immunology.
4. (May 2018). "TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation". Biochemical and Biophysical Research Communications.
5. (April 1999). "Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer". The EMBO Journal.
6. (April 2012). "Sustained RANKL response to parathyroid hormone in oncostatin M receptor-deficient osteoblasts converts anabolic treatment to a catabolic effect in vivo". Journal of Bone and Mineral Research.
7. (December 2001). "Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms". The Journal of Biological Chemistry.
8. (May 2015). "IL-6 as a keystone cytokine in health and disease". Nature Immunology.
9. (August 2003). "Principles of interleukin (IL)-6-type cytokine signalling and its regulation". The Biochemical Journal.
10. (December 2000). "Non-redundant signal transduction of interleukin-6-type cytokines. The adapter protein Shc is specifically recruited to the oncostatin M receptor". The Journal of Biological Chemistry.
11. (January 2008). "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis". American Journal of Human Genetics.
12. (February 2010). "Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice". The Journal of Clinical Investigation.
13. (July 2013). "Lack of oncostatin M receptor β leads to adipose tissue inflammation and insulin resistance by switching macrophage phenotype". The Journal of Biological Chemistry.
14. (November 2003). "Targeted disruption of oncostatin M receptor results in altered hematopoiesis". Blood.
15. (January 2014). "Therapeutic targeting of the oncostatin M receptor-β prevents inflammatory heart failure". Basic Research in Cardiology.
16. (November 2011). "Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling". Cell Stem Cell.
17. (July 2017). "Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling". Oncogene.
18. (November 2006). "Oncostatin M (OSM) cytostasis of breast tumor cells: characterization of an OSM receptor beta-specific kernel". Cancer Research.
19. (July 2007). "Gain and overexpression of the oncostatin M receptor occur frequently in cervical squamous cell carcinoma and are associated with adverse clinical outcome". The Journal of Pathology.
20. (March 2002). "Coexpression of oncostatin M and its receptors and evidence for STAT3 activation in human ovarian carcinomas". Cytokine.
21. (August 2009). "Promoter DNA methylation of oncostatin m receptor-beta as a novel diagnostic and therapeutic marker in colon cancer". PLOS ONE.