CD73 (Cluster of Differentiation 73) and the Differences Between Mice and Humans

Abstract

As vascular disease is complex and the various manifestations are influenced by differences in vascular bed architecture, exposure to shear and mechanical forces, cell types involved, and inflammatory responses, in vivo models are necessary to recapitulate the complex physiology and dynamic cellular interactions during pathogenesis. Murine knockout models are commonly used tools for investigators to study the role of a specific gene or pathway in multifaceted disease traits. Although valuable, these models are not perfect, and this is particularly true in regard to CD73 (cluster of differentiation 73), the extracellular enzyme that generates adenosine from AMP. At baseline, CD73-deficient mice do not present with an overt phenotype, whereas CD73-deficient humans present with the complex phenotype of vascular calcification, arteriomegaly and tortuosity, and calcification in small joints. In this review, we highlight the differences between the mouse and human systems and discuss the potential to leverage findings in mice to inform us on the human conditions.

Keywords: adenosine; cardiovascular disease; mice; rare disease; vascular calcification.

Figure 1.. Summary of the Phenotypic Differences between CD73-deficient Mice and Humans.

At the 11 o’clock position, we represent a patient with ACDC and her associated phenotypes. Symptoms such as joint pain are due to extensive calcifications surrounding joint capsules, perhaps presenting an opportunity to study CD73 in distinct forms of arthritis. Vascular pathology is the predominant phenotype in ACDC with immune cell infiltration, elastic lamina degradation, and medial calcification, all resulting in symptoms and pathologies seen in more common vascular diseases. These phenotypes are in contrast with the murine CD73-deficient models represented by the image at the 4 o’clock position. Unlike their human counterpart, CD73-deficient models do not present with the same vascular pathology. Instead, studies have shown both a decrease and increase in atherosclerosis, and a decrease in time to thrombooclusion. These mice are less able to modulate glomerular arteriolar tone and exhibit more vascular leakage in response to hypoxia. Perhaps the most thoroughly studied, cancer progression is decreased in most CD73-deficient murine studies in part by lymphocyte activity. Lymphocytes have also been shown to worsen heart failure in these models. Finally, these models can develop joint calcification, the only known phenotype that resembles human disease.