Can the NK family of osteoblast homeodomain transcription factors signaling be a magic bullet to reverse calcification-induced vasculopathy in diabetes?

Human vascular calcification burden has existed for at least 5 millennia and has long been a major area of interest in the cardiovascular physiopathology research. Abnormal calcium deposition occurs in almost all arterial beds in both the media and intima in metabolic and diabetic diseases. Calcification of arteries reduces arterial elastance and compromises cardiovascular hemodynamics, which are high risk factors for cardiovascular diseases such stroke and ischemic heart disease (1). Despite the wealth of information regarding the effects of vascular calcification in atherosclerosis, metabolic syndrome, hypertension, and diabetes, the molecular mechanism of arteriosclerosis remains poorly understood. Therefore, understanding the mechanism by which diabetes and metabolic disease induce vascular calcification is crucial to identify effective new therapeutic strategies to intervene with the disease. Interestingly in this issue, Cheng et al. (2) determined the in vivo contribution of members of the highly conserved NK family of osteoblast homeodomain transcription factors 1 (Msx1) and 2 (Msx2) signaling in arteriosclerosis and vascular stiffness in diabetic mice. The study by Cheng et al. provides new insight into the molecular mechanism that drives arteriosclerosis in diabetes and suggests a potential target for future therapy. Thus, targeting Msx1 and Msx2 would substantially help the development of a new therapeutic strategy to overcome calcification-induced vasculopathy. In diabetic patients, vascular calcification occurs mainly in coronary and vascular arteries of lower limbs (3,4). This calcification is associated with an increased prevalence of arteriosclerosis vascular disease and cardiovascular morbidity and mortality. Arteriosclerosis is the thickening, hardening, and loss of elasticity of arterial walls in diabetes, dyslipidemia, and uremia (5). The calcification of arterial media, called Mönckeberg sclerosis or arteriosclerosis, is a characteristic feature of diabetes. Arterial media calcification is a concentric and dynamic process of the tunica media, which compromises vascular homeostasis and represents a high risk factor for cardiovascular diseases (6). Recent evidence indicates that medial calcification in diabetes is an active, cell-mediated process in which vascular smooth muscle cells (VSMCs) express a number of bone matrix proteins involved in the calcification events. Cheng et al. (2) reported that Msx1 and Msx2 play an in vivo important role in vascular calcification. Thus, the inhibition of Msx1 and Msx2, specifically in smooth muscle cells and vascular myofibroblast, using a Cre-Lox knockout mice system substantially reduced aortic calcium deposition and improved pulse wave velocity (an index of stiffness). These events are associated with a reduction in transcription factors essential for osteogenic alleviation of mineralization, osterix, and Sonic hedgehog (Shh) (a marker of the vascular multipotent mesenchymal progenitors). Importantly, the study reported that mice deficient for Msx1 and Msx2 in VSMCs exhibit a significant reduction in aortic calcium accumulation after 2 months of high-fat diabetogenic diet treatment compared with control mice fed with high-fat diet. The same group previously demonstrated in the same model of murine diabetic arteriosclerosis that Msx1 and Msx2 expressions