Biological functions of tumor suppressor M and its research progress in diseases

OSM activates downstream signaling pathways by binding to specific receptors, and participates in regulating key biological processes such as cell proliferation, differentiation, and apoptosis, playing an important regulatory role in various physiological and pathological states.

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Oncostatin M (OSM), an important member of the interleukin-6 (IL-6) cytokine family, has gradually revealed its multiple roles in immune regulation, inflammatory responses, tissue repair, and tumorigenesis and development since it was first isolated and identified from macrophage-conditioned medium in 1986. By binding to specific receptors and activating downstream signaling pathways, OSM participates in regulating key biological processes such as cell proliferation, differentiation, and apoptosis, playing an important regulatory role in various physiological and pathological states. This article systematically elaborates on the molecular structural characteristics, signal transduction mechanisms, biological functions of OSM, as well as its research progress in inflammatory diseases and tumors, providing a comprehensive reference for in-depth understanding of the physiological and pathological significance of this multifunctional cytokine.

1. Molecular Structure and Receptor System of OSM

OSM is a secreted glycoprotein composed of 205 amino acids with a molecular weight of approximately 28 kDa, and its gene is located on the long arm of human chromosome 22 (22q12.2). Its molecular structure contains a typical cytokine domain consisting of four α-helices, among which the region between helix A and helix D is the key site for receptor binding. OSM exists in two main subtypes, namely OSM-α and OSM-β. OSM-α is expressed by various cells, while OSM-β is mainly restricted to T lymphocytes, and the two subtypes have certain differences in tissue distribution and function.

The biological role of OSM is achieved through binding to receptor complexes on the cell membrane surface. Its receptor system is composed of two subunits: the specific receptor OSMRβ and the shared receptor gp130. OSM can function through two receptor combinations: one is forming a high-affinity heterotrimeric complex with OSMRβ and gp130, which is the main form of OSM-specific signal transduction; the other is binding with LIFR (leukemia inhibitory factor receptor) and gp130, and this combination shares part of the signaling pathway with leukemia inhibitory factor (LIF). OSMRβ is widely expressed in various tissues, especially with high expression levels in the liver, kidney, lung, and hematopoietic tissues, providing a histological basis for the multifunctional regulation of OSM.

2. Signal Transduction Mechanism of OSM

After binding to receptors, OSM transmits biological signals by activating multiple signaling pathways, among which the JAK-STAT pathway is the most important signal transduction pathway. After OSM binds to the receptor complex, it induces conformational changes in receptor subunits, leading to the mutual phosphorylation and activation of bound Janus kinases (JAK1, JAK2, and TYK2), which in turn phosphorylate tyrosine residues in the intracellular segment of the receptor, forming binding sites for STAT proteins. STAT3 is the most important downstream effector molecule in OSM signaling. After being recruited and phosphorylated, it forms homodimers or heterodimers with STAT1, translocates into the nucleus, binds to STAT binding elements in the promoter of target genes, and regulates downstream gene expression.

In addition to the JAK-STAT pathway, OSM can also activate MAPK signal cascades, including ERK1/2, p38 MAPK, and JNK pathways, participating in the regulation of cell proliferation and stress responses. Furthermore, OSM affects cell survival and metabolic processes by activating the PI3K-AKT-mTOR pathway, and participates in the regulation of inflammatory responses by activating the NF-κB pathway. These signaling pathways form a complex regulatory network through cross-talk, enabling OSM to precisely regulate downstream biological effects according to different cell types and microenvironmental conditions.

3. Biological Functions of OSM

Under physiological conditions, OSM plays an important role in embryonic development, tissue repair, and immune regulation. During embryonic development, OSM participates in the formation of the liver and skeletal systems, affecting organogenesis by regulating hepatocyte differentiation and osteoblast activity. In the process of tissue repair, OSM is secreted by macrophages and inflammatory cells infiltrating the injury site, promoting fibroblast proliferation and collagen synthesis, accelerating wound healing; at the same time, it regulates vascular endothelial cell activity, promotes neovascularization, and provides nutritional support for tissue repair.

In the immune system, OSM is an important regulatory factor connecting innate immunity and adaptive immunity. It can induce the maturation of macrophages and dendritic cells, enhance antigen-presenting ability; promote the differentiation of T cells into Th17 cells, enhance adaptive immune responses; and regulate B cell proliferation and antibody secretion, participating in humoral immune regulation. In addition, OSM can stimulate the proliferation and differentiation of hematopoietic stem cells in the hematopoietic system, maintaining hematopoietic homeostasis. These extensive biological functions make OSM a key regulatory factor for maintaining the body's physiological balance.

4. Role of OSM in Inflammatory Diseases

As an important pro-inflammatory cytokine, OSM plays a key role in the occurrence and development of various inflammatory diseases. In the synovial tissue of patients with rheumatoid arthritis, the expression level of OSM is significantly increased, which promotes joint synovial inflammation and cartilage destruction by stimulating synovial fibroblasts to secrete inflammatory factors such as IL-6, IL-8, and matrix metalloproteinases (MMPs). Studies have shown that OSM-induced activation of STAT3 and NF-κB pathways is an important molecular mechanism for abnormal activation of synovial cells.

In respiratory diseases, OSM is involved in the pathological processes of chronic obstructive pulmonary disease (COPD) and asthma. OSM secreted by alveolar macrophages in COPD patients can induce airway epithelial cells to produce mucus and promote airway remodeling; in asthma models, OSM exacerbates airway inflammation and hyperresponsiveness by regulating eosinophil infiltration and Th2-type cytokine secretion. In addition, OSM has been confirmed to participate in the progression of chronic inflammatory diseases such as inflammatory bowel disease and psoriasis by enhancing inflammatory responses and tissue damage, becoming a potential anti-inflammatory therapeutic target.

5. Dual Role of OSM in Tumors

The role of OSM in tumors shows significant duality, with both pro-cancer and anti-cancer activities. This contradictory phenomenon is closely related to tumor type, microenvironment, and stage of action. In breast cancer, OSM promotes tumor cell proliferation and metastasis by activating the STAT3 pathway, and induces macrophages in the tumor microenvironment to polarize into M2 type, accelerating tumor progression; in lung cancer models, OSM can enhance the invasiveness and angiogenesis of tumor cells, which is related to poor prognosis.

On the other hand, OSM shows anti-cancer effects in certain tumor types. In leukemia cells, OSM can induce tumor cell differentiation and apoptosis, inhibiting the proliferation of leukemia cells; in ovarian cancer cells, high concentrations of OSM inhibit cell growth by activating the p38 MAPK pathway. This dual role may result from the differential activation of different signaling pathways by OSM, as well as the synergistic or antagonistic effects of other cytokines in the tumor microenvironment. In-depth study of the role of OSM in different tumors is of great significance for the development of OSM-targeted tumor treatment strategies.

6. Detection Methods and Research Prospects of OSM

Current detection methods for OSM mainly include enzyme-linked immunosorbent assay (ELISA), real-time fluorescence quantitative PCR (qPCR), and immunohistochemistry (IHC). The ELISA method can quantitatively detect OSM protein levels in serum, plasma, or tissue culture media, and is widely used in clinical sample analysis; qPCR is used to detect OSM mRNA expression and evaluate its transcriptional regulation; IHC can localize the expression distribution of OSM in tissues, revealing its cell source and pathological localization. These detection technologies provide important tools for the basic research and clinical application of OSM.

With the deepening of research on OSM functions, OSM-targeted therapeutic strategies have become a research hotspot. Neutralizing antibodies against OSM or its receptors have shown good anti-inflammatory effects in rheumatoid arthritis animal models; small molecule inhibitors blocking OSM downstream signaling pathways have shown anti-tumor activity in tumor models. Future research needs to further clarify the specific mechanism of OSM in different diseases and develop more precise targeted therapy regimens. At the same time, the potential of OSM as a disease diagnostic and prognostic marker is also worthy of in-depth exploration, which is expected to provide new biomarkers and therapeutic targets for the precise diagnosis and treatment of inflammatory diseases and tumors.

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