Gpnmb, also known as glycoprotein nonmetastatic melanoma protein B, is an endogenous glycoprotein. It is highly expressed in macrophages and microglia, participating in innate immune response. Gpnmb has been associated with inflammation, neuroinflammation, and is involved in multiple pathways related to various diseases. Genetic models, such as gene knockout mouse models, can be valuable for studying its functions [1].

In Parkinson's disease, colocalization and allele-specific expression studies linked the GWAS-derived chromosome 7 locus to Gpnmb. In cells, Gpnmb co-immunoprecipitated and colocalized with α-synuclein. In induced pluripotent stem cell-derived neurons, loss of Gpnmb led to loss of ability to internalize α-synuclein fibrils and develop α-synuclein pathology. Also, Gpnmb was elevated in PD plasma, associating with disease severity [2].

In renal neoplasms, in cell lines Gpnmb was upregulated following TSC2 loss in a MiT/TFE-and mTORC1-dependent fashion. Mean Gpnmb expression was significantly higher in TFE3/TFEB-driven tRCC than in other types of renal cell carcinomas, and its expression in TSC1/2/MTOR alteration-associated renal tumors was comparable to that in tRCC [3].

In obesity, inhibition of the hepatic sterol regulatory element-binding protein pathway increased Gpnmb transcription. Gpnmb secreted from the liver promoted lipogenesis in white adipose tissue, aggravating obesity and insulin resistance. Inhibition of Gpnmb improved metabolic parameters [4].

In cancer, Gpnmb overexpression in various cancers promoted primary tumor growth, metastasis, and was associated with poor prognosis. It also played an immunosuppressive role [5]. In colorectal liver metastasis, high infiltration of Gpnmb + cells correlated with shorter disease-free survival and overall survival [6]. In glioblastoma, Gpnmb-high macrophages promoted the PN-MES transition of tumor cells and impeded T cell activation [7].

In conclusion, Gpnmb is involved in inflammation, neurodegenerative diseases like Parkinson's, metabolism-related diseases such as obesity, and various cancers. Gene knockout or related genetic models have revealed its diverse functions in these biological processes and disease conditions, providing insights into potential therapeutic targets for these diseases.

References:

1. Saade, Marina, Araujo de Souza, Giovanna, Scavone, Cristoforo, Kinoshita, Paula Fernanda. 2021. The Role of GPNMB in Inflammation. In Frontiers in immunology, 12, 674739. doi:10.3389/fimmu.2021.674739. https://pubmed.ncbi.nlm.nih.gov/34054862/

2. Diaz-Ortiz, Maria E, Seo, Yunji, Posavi, Marijan, Weintraub, Daniel, Chen-Plotkin, Alice S. 2022. GPNMB confers risk for Parkinson's disease through interaction with α-synuclein. In Science (New York, N.Y.), 377, eabk0637. doi:10.1126/science.abk0637. https://pubmed.ncbi.nlm.nih.gov/35981040/

3. Salles, Daniela C, Asrani, Kaushal, Woo, Juhyung, Argani, Pedram, Lotan, Tamara L. 2022. GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms. In The Journal of pathology, 257, 158-171. doi:10.1002/path.5875. https://pubmed.ncbi.nlm.nih.gov/35072947/

4. Gong, Xue-Min, Li, Yun-Feng, Luo, Jie, Qi, Wei, Song, Bao-Liang. 2019. Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance. In Nature metabolism, 1, 570-583. doi:10.1038/s42255-019-0065-4. https://pubmed.ncbi.nlm.nih.gov/32694855/

5. Lazaratos, Anna-Maria, Annis, Matthew G, Siegel, Peter M. 2022. GPNMB: a potent inducer of immunosuppression in cancer. In Oncogene, 41, 4573-4590. doi:10.1038/s41388-022-02443-2. https://pubmed.ncbi.nlm.nih.gov/36050467/

6. Cortese, Nina, Carriero, Roberta, Barbagallo, Marialuisa, Mantovani, Alberto, Marchesi, Federica. . High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis. In Cancer immunology research, 11, 405-420. doi:10.1158/2326-6066.CIR-22-0462. https://pubmed.ncbi.nlm.nih.gov/36652202/

7. Xiong, Aizhen, Zhang, Jiwei, Chen, Yan, Zhang, Yi, Yang, Fan. 2022. Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM. In EBioMedicine, 83, 104239. doi:10.1016/j.ebiom.2022.104239. https://pubmed.ncbi.nlm.nih.gov/36054938/