Identification and characterization of the mediators of the calcification paradox

This thesis focuses on the identification and characterization of novel inhibitors of the pathophysiological process of vascular calcification (VC). By characterization of the novel peptide called “calcification blocking factor (CBF)”, the conditions and concentrations under which this peptide inhibits VC were identified. Next, CBF (1-8), a small fragment of CBF, was identified which is a more potent inhibitor of vascular calcification compared to CBF. This thesis demonstrates the impact of CBF (1-8) on VC and illustrates the mechanisms by which CBF (1-8) inhibits VC. CBF (1-8) is derived from the protein chromogranin A and might be one of the missing links in our current knowledge about the calcification paradox, the loss of bone density under calcification inducing conditions. Moreover, CBF (1-8) is the first peptidic mediator that links VC to bone mineral density in vivo. Understanding the mechanisms by which CBF (1-8) functions will help utilize the regulatory balance between VC and bone mineralization, enabling us to tilt the balance towards bone mineralization by maintaining plasma CBF (1-8) concentration. In addition, the identification and characterization of these previously unknown peptides open novel options for VC therapy without or at least with limited negative impact on bone density.