Do cytokines induce vascular calcification by the mere stimulation of TNAP activity?

Vascular calcification occurs during aging in the general population and is increased in the intima by atherosclerosis and in the media by diabetes type 2. In both intima and media, calcification may lead to the formation of a tissue very similar if not identical to bone, with bone cells and bone marrow. Since vascular calcification is associated with cardiovascular complications, a better understanding of the inducing mechanisms could lead to the development of new therapeutic strategies. Many studies have provided evidence for a role of inflammation and inflammatory cytokines such as tumour necrosis factor (TNF)-α and interleukin (IL)-1β in the vascular calcification process. TNF-α and IL-1β have indeed been shown to stimulate in vitro the expression by vascular smooth muscle cells (VSMCs) of tissue-non specific alkaline phosphatase (TNAP), a key enzyme in the mineralization process, and to trigger the trans-differentiation of VSMCs into osteoblast-like cells, expressing the master transcription factor RUNX2. These data are however somewhat contradictory with the known inhibitory effects of inflammatory cytokines on bone formation. TNF-α for instance dramatically decreases RUNX2 RNA expression, protein stability and activity, and as a consequence, is a potent inhibitor of osteoblast differentiation and bone formation. In the present article, we propose a new hypothesis to explain this calcification paradox. We propose that cytokines block bone formation by decreasing RUNX2-mediated type I collagen production in osteoblasts, whereas they induce vascular ossification by the mere stimulation of TNAP by VSMCs, independently of RUNX2. We propose that this stimulation of TNAP in VSMCs in vitro and in vivo may be sufficient to induce the calcification of collagen fibrils, and that the absence of crystal clearance, in turn, induces the differentiation of VSMCs and/or mesenchymal stem cells into bone-forming cells, eventually leading to formation of a bone-like tissue. In case future experimental studies support this hypothesis, the early stimulatory and late inhibitory effects of inflammation on vascular calcification will have to be taken into consideration in the development of new therapeutic strategies.