See related article, pages 1041–1048 Vascular calcification is a pathological sequence of events that has similarities to the normal physiological process of osteogenesis.1,2 It is thought to result from an imbalance in both local and systemic inhibitors and promoters,3,4 which occurs as a consequence of chronic inflammation, hyperleptinemia, and a deregulation of various bone-regulating proteins. It is common in patients with diabetes and renal failure and in the elderly.4,5 The fact that coronary artery calcification is such a major health problem and the recognition that it is highly correlative with mortality risk6 makes the understanding of vascular calcification a worthy and exciting area of study. In normal skeletal physiology, bone deposition by osteoblasts is in balance with bone resorption by osteoclasts. RANKL (receptor activator of nuclear factor [NF]-κB ligand) and its soluble decoy receptor, osteoprotegerin (OPG), are critical regulators of bone remodeling. Binding of RANKL to its cognate receptor RANK, expressed on osteoclasts and its precursors, induces NF-κB signaling, resulting in NF-κB translocation to the nucleus with a subsequent increase in RelB levels, in turn, stimulating osteoclastic differentiation (Figure, A). OPG, a decoy receptor, expressed by osteoblasts, binds with RANKL, preventing RANK (receptor activator of NF-κB) signaling and thus inhibiting osteoclastogenesis (Figure, B).7 Figure. Bone resorption in the skeleton often coexists with bone formation in the vasculature. A, Binding of RANKL to RANK stimulates osteoclast maturation and destruction of bone through loss of mineral. B, Osteoblasts express OPG the natural decoy receptor for RANKL, preventing RANK activation and inhibiting maturation of osteoclasts thus inhibiting bone resorption. An increased availability of OPG and the block on RANKL signaling supports osteoblast differentiation, maturation, and function allowing the deposition of bone. C, Elevated OPG in the vasculature and increased Ca/P products marks a commitment of …