Tnfsf11, also known as Receptor activator of NF-κB ligand (RANKL), is a key cytokine in the RANKL/RANK/OPG pathway. It plays a crucial role in osteoclast differentiation and activation, which is essential for bone resorption [1,4,6,7]. This pathway is also involved in various physiological and pathological processes, including bone remodeling, immune regulation, and cancer metastasis [1,4,7]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying Tnfsf11's functions.

In lung adenocarcinoma, overexpression of Tnfsf11 reduces GPX4 levels and increases sensitivity to ferroptosis inducers, suggesting its potential as a therapeutic target [2]. In preeclampsia, polymorphisms in the Tnfsf11 gene (rs2200287 and rs2148072) are associated with the disease, indicating its role in pregnancy-related immune regulation [3]. In membranous nephropathy, the miR-149-5p/TNFSF11 pathway is involved in angiotensin II-induced podocyte apoptosis, and knockdown of circ_CDYL can inhibit this process through this pathway [8]. Also, miR-4732-3p inhibits lung cancer progression by targeting the TBX15/TNFSF11 axis [5].

In conclusion, Tnfsf11 is a significant cytokine in the RANKL/RANK/OPG pathway, playing essential roles in bone metabolism, immune response, and cancer development. Studies using KO/CKO mouse models and other functional studies have revealed its functions in various disease conditions such as lung adenocarcinoma, preeclampsia, and membranous nephropathy, providing potential targets for therapeutic intervention.

References:

1. Boyle, William J, Simonet, W Scott, Lacey, David L. . Osteoclast differentiation and activation. In Nature, 423, 337-42. doi:. https://pubmed.ncbi.nlm.nih.gov/12748652/

2. Li, Zizhen, Lu, Wenhua, Yin, Feng, Li, Heping, Huang, Amin. 2024. Overexpression of TNFSF11 reduces GPX4 levels and increases sensitivity to ferroptosis inducers in lung adenocarcinoma. In Journal of translational medicine, 22, 340. doi:10.1186/s12967-024-05112-y. https://pubmed.ncbi.nlm.nih.gov/38594779/

3. Sivaraj, Nagarjuna, Kusuma, Bunga Papa, Kutikuppala, L V Simhachalam, Balaga, Vijaya Sirisha, Gundakaram, Samhitha. 2022. Association of TNFSF11 rs2200287 and TNFSF11 rs2148072 gene polymorphisms in preeclampsia. In American journal of reproductive immunology (New York, N.Y. : 1989), 88, e13604. doi:10.1111/aji.13604. https://pubmed.ncbi.nlm.nih.gov/35869907/

4. Tobeiha, Mohammad, Moghadasian, Mohammed H, Amin, Negin, Jafarnejad, Sadegh. 2020. RANKL/RANK/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling. In BioMed research international, 2020, 6910312. doi:10.1155/2020/6910312. https://pubmed.ncbi.nlm.nih.gov/32149122/

5. Li, Pengfei, Li, Ying, Bai, Shuping, Zhang, Yu, Zhao, Ling. 2023. miR-4732-3p prevents lung cancer progression via inhibition of the TBX15/TNFSF11 axis. In Epigenomics, 15, 195-207. doi:10.2217/epi-2023-0009. https://pubmed.ncbi.nlm.nih.gov/37125501/

6. Ando, Yutaro, Tsukasaki, Masayuki. . [RANKL and periodontitis]. In Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 158, 263-268. doi:10.1254/fpj.22122. https://pubmed.ncbi.nlm.nih.gov/37121710/

7. Nagy, Vanja, Penninger, Josef M. 2015. The RANKL-RANK Story. In Gerontology, 61, 534-42. doi:10.1159/000371845. https://pubmed.ncbi.nlm.nih.gov/25720990/

8. Qiu, Donghao, Zhao, Ning, Chen, Qi, Wang, Ming. 2022. Knockdown of circ_CDYL Contributes to Inhibit Angiotensin II-Induced Podocytes Apoptosis in Membranous Nephropathy via the miR-149-5p/TNFSF11 Pathway. In Journal of cardiovascular pharmacology, 79, 887-895. doi:10.1097/FJC.0000000000001262. https://pubmed.ncbi.nlm.nih.gov/35353073/