OSR2 is a zinc finger structural transcription factor that mainly participates in the embryonic development, bone formation and immune regulation of vertebrates. This protein plays a significant role in key physiological processes such as palatine plate fusion and joint morphogenesis by regulating the expression of downstream target genes. Recent studies have found that OSR2 can act as a mechanical stress sensor in the tumor microenvironment, mediating T cell exhaustion through the Piezo1/calcium ion signaling pathway. This mechanism provides a new target for cancer immunotherapy. As an important molecule in the cross-disciplinary research of developmental biology and immunology, OSR2, due to its unique regulatory network and pathological significance, is becoming a key research object for understanding the mechanisms of tissue development and disease occurrence.
OSR2 is a zinc finger structure transcription factor with a molecular weight of approximately 55-60 kDa, and its precise molecular weight varies slightly among different species and splicing variants. The following is a comparison of the molecular characteristics of the main species:
| Species | Human | Mice | Zebrafish |
| Molecular Weight (kDa) | 58.2 | 57.8 | 56.5 |
| Primary Structural Differences | Conservative zinc finger domain | N end has additional control area | Some regulatory sequences are missing |
This protein is composed of approximately 500 amino acids and contains an N-terminal transcriptional inhibitory domain and a highly conserved zinc finger DNA-binding domain at the C-terminal. Its tertiary structure shows that the zinc finger motif forms a typical "ββα" fold, stabilizing the structure through the coordination of cysteine and histidine residues with zinc ions.
Fig. 1 Mechanism of action of OSR2 mediating Max-regulated decidualization of endometrial stromal cells in recurrent miscarriage.1
Key structural properties of OSR2:
OSR2 is a multifunctional transcriptional regulator whose main functions include developmental regulation and immunomodulation, and also plays a key role in the tumor microenvironment. The following is an overview of its main functions:
| Function | Description |
| Regulation of embryonic development | Regulating the fusion of the palatine plate and the formation of synovial joints is crucial for the development of the skeletal system. |
| Mechanical stress response | As a biomechanical sensor, it transduces mechanical signals through the Piezo1/ calcium ion pathway. |
| Immune regulation | Promote the depletion of CD8+ T cells and affect the efficacy of tumor immunotherapy. |
| Epigenetic regulation | Recruit modification enzymes such as HDAC3 to alter chromatin structure and gene expression profiles. |
| Maintenance of bone homeostasis | Involved in chondrocyte differentiation and metabolic balance of articular cartilage. |
Unlike typical transcription factors, OSR2 exhibits unique dose-dependent regulatory characteristics: at low expression, it mainly exerts developmental regulatory functions, while under pathological conditions such as chronic mechanical stress or tumor microenvironment, its upregulation significantly promotes the formation of an immunosuppressive microenvironment. This dual functional characteristic makes it an important molecular node connecting developmental biology and tumor immunology.
1. Ma, Weixu, et al. "MAX deficiency impairs human endometrial decidualization through down-regulating OSR2 in women with recurrent spontaneous abortion." Cell and Tissue Research 388.2 (2022): 453-469. https://doi.org/10.1007/s00441-022-03579-z
Studies have shown that MAX deficiency damages the proliferation and decidualization of endometrial stromal cells by directly down-regulating the expression of the transcription factor OSR2, leading to recurrent miscarriage. Overexpression of OSR2 can partially reverse the decrease in IGFBP1 expression caused by MAX deletion.
2. Li, Wen-han, et al. "Detection of OSR2, VAV3, and PPFIA3 Methylation in the Serum of Patients with Gastric Cancer." Disease Markers 2016.1 (2016): 5780538. https://doi.org/10.1155/2016/5780538
Research has found that methylation of OSR2, VAV3 and PPFIA3 genes is significantly highly expressed in gastric cancer tissues. The combined sensitivity of serum detection reaches 83.3% and the specificity is 88%, which can be used as potential markers for non-invasive diagnosis of gastric cancer.
3. Uysal, Daniel, et al. "A comprehensive molecular characterization of the 8q22. 2 region reveals the prognostic relevance of OSR2 mRNA in muscle invasive bladder cancer." Plos one 16.3 (2021): e0248342.https://doi.org/10.1371/journal.pone.0248342
Research has found that overexpression of the 8q22.2 regional gene OSR2 is associated with lymph node metastasis and poor prognosis in muscle-invasive bladder cancer (MIBC), and can serve as a potential survival prediction marker.
4. Drews, Christiane, Sabine Senkel, and Gerhart U. Ryffel. "The nephrogenic potential of the transcription factors osr1, osr2, hnf1b, lhx1 and pax8 assessed in Xenopus animal caps." BMC developmental biology 11.1 (2011): 5. https://doi.org/10.1186/1471-213X-11-5
Studies have found that OSR2, as one of the early nephrogenic transcription factors, is rapidly expressed under the induction of Activin A and participates in the regulatory network of anterior kidney development. However, its sole overexpression is insufficient to induce anterior kidney formation.
5. Huang, Zhuo, et al. "Mesenchymal Mycn participates in odontoblastic lineage commitment by regulating Krüppel-like Factor 4 (Klf4) in mice." Stem Cell Research & Therapy 13.1 (2022): 78. https://doi.org/10.1186/s13287-022-02749-8
By constructing MycnOsr2 gene knockout mice, the study found that mesenchymal Mycn directly regulates Klf4 to regulate the differentiation of dental papilla cells into odontoblasts, while OSR2-CRE-mediated Mycn deficiency leads to defects in dentin formation.
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