Fhl2, also known as LIM protein FHL2, is a member of the LIM-only family. As a multifunctional adaptor and scaffolding protein, it can interact with various molecules like cell surface receptors, kinases, and transcription factors. It is involved in numerous functional activities such as cell proliferation, apoptosis, adhesion, migration, and gene expression. It participates in pathways like EGF/EGFR/YAP, Hippo/YAP, and is related to processes like epithelial-mesenchymal transition. Its biological importance spans across multiple tissues and is crucial for normal physiological functions as well as in disease contexts [1,2,3]. Genetic models, especially knockout mice, have been valuable in studying its functions.

In Fhl2 knockout (KO) mouse models, several significant findings have emerged. Fhl2 deficiency in female mice impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells, highlighting its role in female reproduction [4]. In the context of chronic kidney disease, inhibition of FHL2 expression in FHL2-null mice averts the transdifferentiation of vascular smooth muscle cells into an osteogenic phenotype and mitigates aortic calcification, suggesting FHL2 as a potential target for treating arterial calcification in CKD patients [5]. In lung adenocarcinoma, knockout of FHL2 in cancer-associated fibroblasts reduces their ability to promote metastasis and angiogenesis of lung adenocarcinoma cells in an orthotopic model, indicating its role in cancer progression [6].

In conclusion, Fhl2 plays essential roles in multiple biological processes including female fertility, arterial medial calcification, and cancer progression. The Fhl2 KO mouse models have been instrumental in revealing these functions, contributing to our understanding of diseases related to these processes, and potentially guiding the development of new therapeutic strategies for conditions such as female subfertility, chronic kidney disease-related arterial calcification, and lung adenocarcinoma.

References:

1. Zhang, Jiawei, Zeng, Qun, She, Meihua. 2023. The roles of FHL2 in cancer. In Clinical and experimental medicine, 23, 3113-3124. doi:10.1007/s10238-023-01076-3. https://pubmed.ncbi.nlm.nih.gov/37103649/

2. Wixler, Viktor. 2019. The role of FHL2 in wound healing and inflammation. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 7799-7809. doi:10.1096/fj.201802765RR. https://pubmed.ncbi.nlm.nih.gov/30939249/

3. Verset, Laurine, Feys, Lynn, Trépant, Anne-Laure, De Wever, Olivier, Demetter, Pieter. 2015. FHL2: a scaffold protein of carcinogenesis, tumour-stroma interactions and treatment response. In Histology and histopathology, 31, 469-78. doi:10.14670/HH-11-709. https://pubmed.ncbi.nlm.nih.gov/26676939/

4. Wang, Chen, Sun, Hui, Davis, John S, Yang, Liguo, Hua, Guohua. 2023. FHL2 deficiency impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells. In Cell death & disease, 14, 239. doi:10.1038/s41419-023-05759-3. https://pubmed.ncbi.nlm.nih.gov/37015904/

5. Liao, Yuan-Ru, Tsai, Yu-Cheng, Hsieh, Tsung-Han, Chu, Pao-Hsien, Li, Szu-Yuan. . FHL2 in arterial medial calcification in chronic kidney disease. In Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 39, 2025-2039. doi:10.1093/ndt/gfae091. https://pubmed.ncbi.nlm.nih.gov/38664060/

6. Kanzaki, Ryu, Reid, Steven, Bolivar, Paulina, Shintani, Yasushi, Pietras, Kristian. 2024. FHL2 expression by cancer-associated fibroblasts promotes metastasis and angiogenesis in lung adenocarcinoma. In International journal of cancer, 156, 431-446. doi:10.1002/ijc.35174. https://pubmed.ncbi.nlm.nih.gov/39244734/