Grem2, also known as Gremlin 2 or protein related to Dan and cerberus (PRDC), is a secreted factor and a bone morphogenetic protein (BMP) antagonist. It is involved in multiple biological processes such as osteogenesis, adipogenesis, and tooth development, and is associated with pathways like TGFβ, BMP4/7-SMAD1/5/8, and JNK signaling [1,3,4,5,6]. Genetic models, especially mouse models, have been crucial in understanding its functions.

In mouse models, Grem2 inactivation led to increased trabecular bone mass due to stimulated osteoblast differentiation, suggesting its potential as a target for osteoporosis treatment [3]. Grem2 -/- mice had malformed incisors, indicating its requirement for normal tooth morphogenesis [6]. In visceral preadipocytes, Grem2-overexpressed mice had reduced browning ability of visceral fat, while Grem2 ablation enhanced it, suggesting its role in regulating visceral adiposity [1]. In high-glucose-induced podocyte apoptosis, Grem2 silencing partially protected podocytes, demonstrating its role in this process [2].

In conclusion, Grem2 plays essential roles in bone development, tooth morphogenesis, adipocyte browning, and podocyte apoptosis. The use of Grem2 knockout mouse models has significantly contributed to understanding its functions in osteoporosis, tooth agenesis, central obesity, and diabetic nephropathy, providing potential targets for treatment in these disease areas.

References:

1. Liu, Wen, Li, Danjie, Yang, Minglan, Hong, Jie, Wang, Jiqiu. 2022. GREM2 is associated with human central obesity and inhibits visceral preadipocyte browning. In EBioMedicine, 78, 103969. doi:10.1016/j.ebiom.2022.103969. https://pubmed.ncbi.nlm.nih.gov/35349825/

2. Wen, Hongxiu, Kumar, Vinod, Mishra, Abheepsa, Malhotra, Ashwani, Singhal, Pravin C. 2019. Grem2 mediates podocyte apoptosis in high glucose milieu. In Biochimie, 160, 113-121. doi:10.1016/j.biochi.2019.02.015. https://pubmed.ncbi.nlm.nih.gov/30831151/

3. Nilsson, Karin H, Henning, Petra, Wu, Jianyao, Ohlsson, Claes, Movérare-Skrtic, Sofia. 2024. GREM2 inactivation increases trabecular bone mass in mice. In Scientific reports, 14, 12967. doi:10.1038/s41598-024-63439-4. https://pubmed.ncbi.nlm.nih.gov/38839844/

4. Mostowska, A, Biedziak, B, Zadurska, M, Firlej, E, Jagodziński, P P. 2017. GREM2 nucleotide variants and the risk of tooth agenesis. In Oral diseases, 24, 591-599. doi:10.1111/odi.12793. https://pubmed.ncbi.nlm.nih.gov/28992378/

5. Williams, Meredith, Zeng, Yu, Chiquet, Brett, Akyalcin, Sercan, Letra, Ariadne. 2021. Functional characterization of ATF1, GREM2 AND WNT10B variants associated with tooth agenesis. In Orthodontics & craniofacial research, 24, 486-493. doi:10.1111/ocr.12462. https://pubmed.ncbi.nlm.nih.gov/33369218/

6. Vogel, P, Liu, J, Platt, K A, Vance, R B, Brommage, R. 2014. Malformation of incisor teeth in Grem2⁻/⁻ mice. In Veterinary pathology, 52, 224-9. doi:10.1177/0300985814528218. https://pubmed.ncbi.nlm.nih.gov/24686385/