Grem1, also known as Gremlin 1, is a BMP-antagonist. It belongs to a family of secreted cysteine-knot proteins that sequester and inhibit bone morphogenetic proteins (BMPs), preventing BMP-mediated receptor activation. Grem1 is involved in multiple biological processes such as embryonic development, organogenesis, and tissue differentiation [4,5].

In mouse models, ablation of Grem1-lineage cells causes osteoarthritis (OA), suggesting that OA may be due to the attrition of Grem1-expressing articular cartilage progenitor cells. FGFR3 signalling, which sustains these cells, was identified as a potential therapeutic pathway for OA [1]. In pancreatic cancer, Grem1 inactivation in established PDAC in mice led to the conversion of epithelial into mesenchymal PDAC cells, indicating its role in maintaining cellular heterogeneity [2]. In intervertebral disc degeneration (IVDD), the expression of Grem1 was positively correlated with the severity of IVDD, and Grem1 siRNA could inhibit Grem1-induced apoptosis and extracellular matrix alterations by mediating the TGF-β/Smad signalling pathway [3].

In summary, Grem1 is crucial in maintaining cellular heterogeneity in pancreatic cancer, is involved in the development of OA and IVDD. Gene-knockout or conditional-knockout mouse models have been instrumental in revealing Grem1's role in these disease conditions, providing potential targets for therapeutic intervention in these areas.

References:

1. Ng, Jia Q, Jafarov, Toghrul H, Little, Christopher B, Woods, Susan L, Mukherjee, Siddhartha. 2023. Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis. In Nature communications, 14, 6909. doi:10.1038/s41467-023-42199-1. https://pubmed.ncbi.nlm.nih.gov/37907525/

2. Lan, Linxiang, Evan, Theodore, Li, Huafu, Sadanandam, Anguraj, Behrens, Axel. 2022. GREM1 is required to maintain cellular heterogeneity in pancreatic cancer. In Nature, 607, 163-168. doi:10.1038/s41586-022-04888-7. https://pubmed.ncbi.nlm.nih.gov/35768509/

3. Chen, Shunlun, Lei, Linchuan, Li, Zemin, Zheng, Zhaomin, Wang, Jianru. 2022. Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylation. In Experimental & molecular medicine, 54, 518-530. doi:10.1038/s12276-022-00753-9. https://pubmed.ncbi.nlm.nih.gov/35440754/

4. Gao, Zhichun, Houthuijzen, Julia M, Ten Dijke, Peter, Brazil, Derek P. 2023. GREM1 signaling in cancer: tumor promotor and suppressor? In Journal of cell communication and signaling, 17, 1517-1526. doi:10.1007/s12079-023-00777-4. https://pubmed.ncbi.nlm.nih.gov/37615860/

5. Zhu, Dantong, Zhao, Dong, Wang, Naixue, Jiang, Mingzhe, Zheng, Zhendong. 2023. Current status and prospects of GREM1 research in cancer (Review). In Molecular and clinical oncology, 19, 69. doi:10.3892/mco.2023.2665. https://pubmed.ncbi.nlm.nih.gov/37614374/