Itm2a, or integral membrane protein 2A, is a transmembrane protein expressed in various tissues. Its function is not fully understood, but it has been associated with several biological processes. It may play roles in cellular differentiation pathways, as it has been linked to osteogenic, chondrogenic, and adipogenic differentiations [1,5,6]. It also seems to be involved in immune-related pathways considering its associations with autoimmune and inflammatory diseases [4,7]. Genetic models such as gene knockout or conditional knockout mouse models can be valuable for studying Itm2a's function.

In bone fracture healing, Itm2a-expressing cells in the periosteum (Itm2a+ P-SSCs) have clonal multipotency and self-renewal, contributing to osteoblasts, chondrocytes, and marrow stromal cells. Ablation of Itm2a+ P-SSCs leads to defects in fracture healing, indicating its importance in this process [1]. In breast and bladder cancers, high Itm2a expression has tumor-suppressing effects. In breast cancer, overexpression inhibits cell proliferation, invasion, and migration, and in bladder cancer, reinstating Itm2a expression impedes malignant behaviors by inhibiting STAT3 activation [2,3]. In 3T3-L1 adipocyte differentiation, Itm2a silencing enhances differentiation, suggesting its role in adipose metabolism [5].

In conclusion, Itm2a is involved in multiple biological processes including bone repair, cancer progression, and adipocyte differentiation. Studies using KO/CKO mouse models have revealed its significance in these areas, providing potential targets for treating skeletal disorders, cancers, and metabolic diseases related to adipose dysregulation.

References:

1. Xing, Wenhui, Feng, Heng, Jiang, Bo, Zhou, Bo O, Zou, Weiguo. 2024. Itm2a expression marks periosteal skeletal stem cells that contribute to bone fracture healing. In The Journal of clinical investigation, 134, . doi:10.1172/JCI176528. https://pubmed.ncbi.nlm.nih.gov/39225088/

2. Zhang, Rui, Xu, Tao, Xia, Yu, Li, Xingrui, Chen, Wen. 2021. ITM2A as a Tumor Suppressor and Its Correlation With PD-L1 in Breast Cancer. In Frontiers in oncology, 10, 581733. doi:10.3389/fonc.2020.581733. https://pubmed.ncbi.nlm.nih.gov/33680917/

3. Jiang, Jiahao, Xu, Jinming, Ou, Longhua, Wang, Yan, Shi, Bentao. 2024. ITM2A inhibits the progression of bladder cancer by downregulating the phosphorylation of STAT3. In American journal of cancer research, 14, 2202-2215. doi:10.62347/KHCC9690. https://pubmed.ncbi.nlm.nih.gov/38859860/

4. Cho, Won K, Baek, In-Cheol, Kim, Sung E, Kim, Tai-Gyu, Suh, Byung-Kyu. . Association of ITM2A rs1751094 polymorphism on X chromosome in Korean pediatric patients with autoimmune thyroid disease. In Immunity, inflammation and disease, 11, e800. doi:10.1002/iid3.800. https://pubmed.ncbi.nlm.nih.gov/36988246/

5. Davies, Stephanie J, Ryan, James, O'Connor, Patrick B F, O'Connor, Rosemary, McCarthy, Tommie V. 2017. Itm2a silencing rescues lamin A mediated inhibition of 3T3-L1 adipocyte differentiation. In Adipocyte, 6, 259-276. doi:10.1080/21623945.2017.1362510. https://pubmed.ncbi.nlm.nih.gov/28872940/

6. Lari, Arezou, Gholami Pourbadie, Hamid, Jafari, Mohieddin, Jamshidi, Ahmadreza, Mahmoudi, Mahdi. 2021. Downregulation of ITM2A Gene Expression in Macrophages of Patients with Ankylosing Spondylitis. In International archives of allergy and immunology, 182, 1113-1121. doi:10.1159/000516179. https://pubmed.ncbi.nlm.nih.gov/34161951/

7. Ye, Xiao-Ping, Yuan, Fei-Fei, Zhang, Le-Le, Liang, Jun, Zheng, Cui-Xia. . ITM2A Expands Evidence for Genetic and Environmental Interaction in Graves Disease Pathogenesis. In The Journal of clinical endocrinology and metabolism, 102, 652-660. doi:10.1210/jc.2016-2625. https://pubmed.ncbi.nlm.nih.gov/27809695/