OSMR: Dual anti-inflammatory and anti-fibrotic therapeutic effects 

• Gene Information: Oncostatin M receptor (OSMR, also known as IL-31R-beta) is a protein-coding gene located on chromosome 5p13.1. It encodes a transmembrane receptor subunit belonging to the type I cytokine receptor family (IL-6 receptor family). 
• Protein Expression: OSMR is expressed on osteoblasts, mesenchymal, and endothelial cells and dorsal root ganglion (DRG) neurons. Its expression is strongly upregulated under inflammatory conditions.
•  Signaling Pathway: Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family produced by osteoblasts, bone marrow macrophages, and neutrophils. OSM acts via two heterodimeric receptors comprising GP130 with either an OSM receptor (OSMR) or a leukemia inhibitory factor receptor (LIFR). 
• Therapeutic Inhibition: By targeting and blocking OSMR (e.g., via anti-OSMR monoclonal antibodies such as vixarelimab), downstream inflammatory cascade and itch signaling are suppressed. This improves clinical outcomes in diseases such as atopic dermatitis, prurigo nodularis, and inflammatory bowel disease (IBD).

OSM 

• The mouse Osm gene that encode the full-length protein was replaced by human OSM counterpart gene sequences in B-hOSM/hOSMR mice.
•  The endogenous mouse promoter, 5′ UTR, and 3′ UTR regions are retained, allowing human OSM expression to be driven by the native mouse Osm promoter, while endogenous mouse Osm transcription and translation are abolished. 

OSMR

•  A chimeric CDS encoding the human OSMR extracellular fused to the mouse OSMR transmembrane and cytoplasmic domain, followed by the mouse 3′ UTR and stop codon, is inserted immediately downstream of the mouse Osmr signal peptide to replace part of exon 2 of the endogenous Osmr gene.
•  Expression of the chimeric OSMR protein is driven by the native mouse Osmr promoter, while endogenous mouse Osmr transcription and translation are disrupted. B-hOSM/hOSMR mice were obtained by breeding B-hOSMR mice with B-hOSM mice.

Strain specific analysis of OSMR gene expression in wild-type mice and B-hOSM/hOSMR mice. Kidney was collected from wild-type C57BL/6 mice (+/+) and homozygous B-hOSM/hOSMR mice (H/H), and analyzed by RT-PCR and western blot. (A) mRNA expression. Mouse Osmr mRNA was exclusively detectable in wild-type mice. Human OSMR mRNA was exclusively detectable in homozygous B-hOSM/hOSMR mice. (B) Protein expression. The OSMR protein were detected both in wild-type mice and homozygous B-hOSM/hOSMR mice. 293T cells were used as positive control (PC).

Strain specific OSM expression analysis in homozygous B-hOSM/hOSMR mice by ELISA. Spleen were isolated from wild-type C57BL/6 mice (+/+) and homozygous B-hOSM/hOSMR mice (H/H), and stimulated with anti-mouse CD3 and anti-mouse CD28 antibodies in vitro. Cell culture supernatant were collected and analyzed by species-specific OSM ELISA kit. Mouse OSM was detectable in wild-type mice. Human OSM was exclusively detectable in homozygous B-hOSM/hOSMR mice but not in wild-type mice. ND: Not detected.

Human OSM induced IL-6 secretion is blockade by anti-hOSMR antibody in MEFs of homozygous B-hOSM/hOSMR mice. Mouse embryonic fibroblasts (MEFs) were derived from either C57BL/6 mice or B-hOSM/hOSMR mice, and stimulated with different concentrations of mOSM (0-100ng/mL) or hOSM (0-1000ng/mL) for 24h. Supernatants from each well were collected and analyzed for IL-6 expression by ELISA. (A) In the MEFs of C57BL/6 mice, IL-6 can be induced by mOSM in a dose-dependent manner, but not by hOSM. It demonstrates that hOSM can’t be recognized by mouse receptor. (B) In the MEFs of B-hOSM/hOSMR mice, hOSM can induce IL-6 secretion, and the function can be blocked by anti-hOSMR antibodies (in house). The results show that the OSMR signaling function was not influenced by gene humanization. Cells were incubated with antibodies (10μg/mL) for 30 minutes, and stimulated with hOSM.

Analysis of leukocyte subpopulations by flow cytometry in immune organs and blood. Splenocytes, peripheral blood, and lymph nodes were isolated from female C57BL/6, B-hOSM/hOSMR mice, B-hIL31/hIL31RA/hOSMR mice and B-hIL31/hIL31RA/hOSM/hOSMR mice (female, 6 or 7-week-old, n = 3). Single live cells were gated on the CD45⁺ population and analyzed by flow cytometry as indicated. Values are expressed as mean ± SEM.

Analysis of T-cell subpopulations by flow cytometry in immune organs and blood. Splenocytes, peripheral blood, and lymph nodes were isolated from female C57BL/6, B-hIL31/hIL31RA/hOSMR mice, B-hOSM/hOSMR mice and B-hIL31/hIL31RA/hOSM/hOSMR mice (female, 6 or 7-week-old, n = 3). Single live cells were gated on the CD3⁺ T-cell population and analyzed by flow cytometry as indicated. Values are expressed as mean ± SEM.