Rcan2, also known as regulator of calcineurin 2, is a physiological inhibitor of the calcineurin-nuclear factor of activated T cells signaling pathway. This pathway controls the differentiation and function of osteoclasts and osteoblasts. Rcan2 expression is regulated by T(3), which is crucial for skeletal development and bone turnover [4]. It also seems to be involved in pathways related to body weight regulation, food intake, and tumor-related processes [2,5].

In gene-knockout mouse models, Rcan2-/-mice showed normal linear growth but had delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development, along with increased mineralization of adult bone. These defects were due to an isolated osteoblast function defect [4]. In another study, inactivation of the Rcan2 gene in mice ameliorated age-and diet-induced obesity by reducing food intake rather than increasing energy expenditure. Rcan2 expression was prominent in hypothalamic nuclei governing energy balance, and loss of Rcan2 attenuated the hyperphagic response to starvation. Rcan2 and leptin were shown to regulate body weight through different pathways [5].

In gastric cancer, RCAN2-positive tumors were more advanced in TNM classification and tumor stage. RCAN2 was an independent prognostic classifier, and its siRNA-mediated knockdown reduced cell growth and invasiveness, inhibiting AKT and p44/p42 (ERK1/2) phosphorylation [1]. In colorectal cancer, RCAN2 was poorly expressed in cancer tissues and cells, especially in cancer stem cells. Its restoration reduced calcineurin activity, promoted NFATC1 phosphorylation and degradation, and decreased stemness of cancer stem cells [3].

In conclusion, Rcan2 plays essential roles in bone development by regulating osteoblast function, in body weight regulation by influencing food intake, and in tumor-related processes such as gastric cancer progression and colorectal cancer stem cell property. Gene-knockout mouse models have been instrumental in revealing these functions, providing valuable insights into the mechanisms underlying bone-related disorders, obesity, and certain cancers.