Itm2a, an integral membrane protein, has diverse functions in multiple biological processes. It's expressed in various tissues, and its functions range from being potentially involved in cell differentiation and development to playing roles in disease-related processes. Its expression is regulated by transcription factors like GATA-3 and Pax3 [5,6].

In bone, Itm2a + periosteal skeletal stem cells (P-SSCs) possess clonal multipotency and self-renewal, contributing to osteoblasts, chondrocytes, and marrow stromal cells during fracture healing. Ablation of Itm2a + P-SSCs leads to fracture healing defects, indicating its importance in bone repair [1]. In cancer, high Itm2a expression acts as a tumor suppressor. In breast cancer, it inhibits cell proliferation, invasion, and migration, and is associated with longer patient survival. It also induces PD-L1 expression accompanied by higher tumor-infiltrating lymphocytes. In bladder cancer, Itm2a suppresses tumor progression by down-regulating STAT3 phosphorylation [2,3]. In adipocyte differentiation, Itm2a overexpression moderately inhibits 3T3-L1 preadipocyte differentiation, while its knockdown enhances differentiation, suggesting its role in adipose tissue metabolism [4].

In summary, Itm2a plays crucial roles in bone fracture healing, cancer progression, and adipocyte differentiation. Studies using genetic models, especially in the context of bone and cancer, have provided valuable insights into its functions, highlighting its potential as a target for treating skeletal disorders and cancer.