Mgp, short for Matrix Gla protein, is a vitamin K-dependent, post-translationally modified protein. It was originally identified as a physiological suppressor of ectopic calcification, highly expressed in vascular and cartilaginous tissues, acting as a potent inhibitor of extracellular matrix mineralization [2,4,6]. Mutations in the Mgp gene can lead to Keutel syndrome, an autosomal recessive disorder characterized by abnormal calcifications in various tissues [4,6]. It has also been implicated in multiple biological processes such as cell differentiation, development, and tumorigenesis, and is associated with pathways like the NF-κB pathway [1,5].

In cancer research, Mgp has been found to have diverse roles. In colorectal cancer, Mgp promotes CD8+ T cell exhaustion by activating the NF-κB pathway, leading to liver metastasis. Inhibition of Mgp in a mouse model of CRC liver metastasis significantly decreased the metastasis rate, and combined with αPD1, it further reduced metastasis [1]. In colon cancer, Mgp promotes cell proliferation by enriching intracellular calcium concentration and activating the NF-κB pathway, and is associated with a worse prognosis [5]. In breast cancer, Mgp+ tumor-associated macrophages influence the efficacy of immunotherapy, with increased numbers of these cells upregulating pro-tumorigenic factors after anti-PD-1 treatment [3]. Regarding skeletal development, heterozygous variants in Mgp altering the Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia. Heterozygous 'knock-in' mice expressing the C19F MGP recapitulate most of the skeletal anomalies observed in affected individuals, suggesting endoplasmic reticulum stress-induced apoptosis of growth plate chondrocytes as the main mechanism [2].

In conclusion, Mgp is crucial in regulating extracellular matrix mineralization, and its dysregulation is associated with various diseases. Studies using mouse models, such as gene knock-in or inhibition in cancer models, have revealed its role in cancer metastasis, cell proliferation, and immune response, as well as in skeletal dysplasia. These findings provide insights into the underlying mechanisms of these diseases and potential therapeutic targets related to Mgp.