The β subunit of the tumor suppressor-M receptor (OSMR) is the β subunit of the interleukin-31 receptor. It binds to IL31RA to form the IL31 receptor. Binding to IL31 activates STAT3 and may also activate STAT1 and STAT5. OSMR dimerizes with gp130 protein, enabling the transduction of OSM-specific signaling events. This makes OSMR a core molecule connecting the two important signaling pathways of OSM and IL-31.

OSMR expression distribution

OSMR is mainly expressed in type 1 alveolar cells, mucous gland cells, endothelial cells, and type 2 alveolar cells. Its expression is abnormally upregulated in various disease states, including those affecting the skin, nervous system, and digestive tract. Its expression is closely related to key pathophysiological processes such as inflammatory responses, cell proliferation, and immune regulation.

(Data source: unprot)

The Structure of OSMR

OSMR is a transmembrane protein composed of 979 amino acids, consisting of an extracellular region, a transmembrane region, and an intracellular region.

Extracellular region: Contains the cytokine receptor homologous domain, responsible for binding to ligands OSM or IL-31. This region has multiple glycosylation sites, and its actual molecular weight (approximately 105-120 kDa) is larger than the molecular weight predicted based on the amino acid sequence (82.8 kDa), mainly due to post-translational glycosylation modifications.

Transmembrane region: A single-transmembrane structure that anchors the receptor to the cell membrane.

Intracellular region: Contains multiple functional domains that interact with downstream signaling molecules, especially the region that binds to JAK kinase, which is crucial for signal transduction.

(Data source: uniprot)

OSMR signaling pathways and regulation

OSMR participates in regulating gene expression and cellular function by activating multiple intracellular signaling pathways. When ligands (OSM or IL-31) bind to OSMR and its co-receptors, receptor dimerization and conformational changes are triggered, thereby activating downstream signaling cascades. By activating the JAK/STAT, MAPK/ERK, PI3K/AKT, and JNK signaling pathways, OSMR promotes cell proliferation, differentiation, metabolism, and migration.

In tumor immune regulation, OSMR promotes tumor proliferation and development. In cardiovascular disease, it promotes the formation and development of aortic plaques. It participates in liver inflammation and fibrosis, and is also involved in hepatocyte regeneration.

(Data source: Wolf CL, et al. Front Immunol. 2023)

Targeted therapy for OSMR

Inhibiting OSMR function in cancer. For example, developing neutralizing antibodies or small molecule inhibitors of OSMR holds promise for blocking its-driven tumor growth, metastasis, and drug resistance.

Vixarelimab is a monoclonal antibody targeting OSMR, co-developed by Roche and Kiniksa Pharmaceuticals. It blocks OSM and IL-31 signaling while preserving signaling through the LIFR pathway. Dysregulation of OSM and/or OSMRβ has been observed in various human diseases and may drive fibrosis, inflammation, and other pathological processes in affected tissues. Vixarelimab is indicated for multiple conditions, including idiopathic pulmonary fibrosis/systemic sclerosis-associated interstitial lung disease (IPF and SSc-ILD) and inflammatory bowel disease (IBD), and is currently in Phase 2 clinical trials.

(Data source: Roche official website)