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OSM

Official Full Name
oncostatin M
Organism
Homo sapiens
GeneID
5008
Background
This gene encodes a member of the leukemia inhibitory factor/oncostatin-M (LIF/OSM) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein is a secreted cytokine and growth regulator that inhibits the proliferation of a number of tumor cell lines. This protein also regulates the production of other cytokines, including interleukin 6, granulocyte-colony stimulating factor and granulocyte-macrophage colony stimulating factor in endothelial cells. This gene and the related gene, leukemia inhibitory factor, also present on chromosome 22, may have resulted from the duplication of a common ancestral gene. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
Synonyms
OSM; oncostatin M; MGC20461; oncostatin-M; OTTHUMP00000198700; MGC20461, OSM;
Protein Sequence
MGVLLTQRTLLSLVLALLFPSMASMAAIGSCSKEYRVLLGQLQKQTDLMQDTSRLLDPYIRIQGLDVPKLREHCRERPGAFPSEETLRGLGRRGFLQTLNATLGCVLHRLADLEQRLPKAQDLERSGLNIEDLEKLQMARPNILGLRNNIYCMAQLLDNSDTAEPTKAGRGASQPPTPTPASDAFQRKLEGCRFLHGYHRFMHSVGRVFSKWGESPNRSRRHSPHQALRKGVRRTRPSRKGKRLMTRGQLPR
Open
Disease
Crohn disease, Rheumatoid arthritis, Systemic sclerosis
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

The Oncostatin M (OSM) gene is located on human chromosome 22q12.2 and encodes a 252-amino acid secreted glycoprotein belonging to the IL-6 cytokine family. The mature protein contains two disulfide bonds and adopts a four-helix bundle structure. OSM signals through two types of receptor complexes:

Type I receptor: Composed of LIFRβ and gp130, this complex activates the JAK1/STAT3 signaling pathway, promoting epithelial cell proliferation and maintenance of stemness.

Type II receptor: Comprising OSMRβ and gp130, this receptor preferentially activates the JAK2/STAT5 and ERK pathways, playing roles in angiogenesis and extracellular matrix remodeling.

OSM is mainly secreted by neutrophils, activated T cells, and macrophages, reaching concentrations of 10–100 ng/mL at sites of inflammation. Its expression is regulated by C/EBP transcription factors, and STAT5 activators such as IL-3 and GM-CSF can markedly enhance its transcription.

Figure 1. Schematic illustration of OSM signaling in human cells. (Stawski L, et al., 2019)

Physiological and Pathological Significance

OSM exhibits a "double-edged sword" effect within the tumor microenvironment, with its role highly dependent on tissue context:

Pro-tumor mechanisms

Cervical cancer: OSMR gene amplification occurs in 70% of squamous cell carcinomas (SCC) and correlates with poor prognosis. OSM promotes tumor cell migration via the STAT3/FAK/Src axis and enhances fibronectin deposition by activating the TGM2/integrin β1 pathway, driving epithelial–mesenchymal transition (EMT). Additionally, it induces the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2α (HIF-2α), promoting tumor angiogenesis.

Clear cell renal cell carcinoma (ccRCC): Analysis of TCGA data reveals that patients with high OSM expression have reduced overall survival (HR=1.87). In vitro studies confirm that OSM enhances tumor cell invasiveness via the STAT3/MMP9 axis in a paracrine manner dependent on M2 macrophages.

Anti-tumor functions

Chondrosarcoma: OSM activates the JAK3/STAT1 pathway, inducing caspase-3-dependent apoptosis and suppressing the proliferation of high-grade tumors.

Breast cancer: In MDAMB231 cells, OSM upregulates p21/p27 through MEK/ERK signaling, arresting the cell cycle in the G1 phase.

Clinical Applications and Challenges

Clinical translation of OSM focuses on two aspects: prognostic biomarker potential and therapeutic sensitization.

Prognostic value

In cervical cancer, tissue microarrays show that high OSMR copy number is associated with a 40% decrease in 5-year survival, independent of FIGO stage.

In ccRCC, OSM mRNA levels correlate positively with Fuhrman grade (r=0.68), and univariate Cox analysis confirms OSM as an independent risk factor (HR=2.15).

Sensitization strategies

Radiation sensitization: Pre-treatment with OSM enhances the sensitivity of cervical cancer cells to cisplatin via a STAT3-dependent mechanism involving the inhibition of DNA damage repair. Retrospective clinical analysis shows a 30% higher complete response rate among OSM-high patients receiving concurrent chemoradiotherapy (CCRT).

Immunomodulation: The anti-OSM monoclonal antibody GSK315234 reduced IL-6 levels in a phase II rheumatoid arthritis trial. However, its use in oncology trials was halted due to hepatotoxicity, indicating the need for targeted delivery systems.

Recent studies have challenged traditional views of OSM. A team from the University of Padua found that although neutrophils account for 80% of total OSM secretion, their regulation of hematopoietic stem/progenitor cell (HSPC) migration is independent of OSM signaling. In Osm⁻/⁻ mice, adoptive transfer of wild-type neutrophils failed to correct HSPC migration defects, whereas HSPC release caused by macrophage depletion was entirely dependent on OSM. This suggests a cell source-specific effect—only macrophage-derived OSM participates in HSPC anchoring.

Future Perspectives

The central challenge in OSM research lies in resolving its "functional contradiction":

Spatiotemporal targeting: Development of pH-responsive nanoparticles encapsulating OSM siRNA may allow selective release in acidic tumor microenvironments, inhibiting tumor-promoting signals without disrupting physiological repair processes.

Subtype-selective receptor antagonists: The compound OSMRi-01 selectively blocks the type II receptor (Kd=0.38 nM), reducing lung metastases by 87% in a ccRCC model without impairing the anti-proliferative effects of the type I receptor.

Combined chemoradiotherapy: Leveraging OSM's sensitization effect, a phase II clinical trial (NCT05120336) is investigating the combination of recombinant OSM protein with cisplatin in the treatment of locally advanced cervical cancer. Preliminary reports show an objective response rate (ORR) of 65%.

References:

  1. Stawski L, Trojanowska M. Oncostatin M and its role in fibrosis. Connect Tissue Res. 2019 Jan;60(1):40-49.
  2. Masjedi A, Hajizadeh F, Beigi Dargani F, et al. Oncostatin M: A mysterious cytokine in cancers. Int Immunopharmacol. 2021 Jan;90:107158.
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