Vascular calcification plays a role in the pathogenesis of atherosclerosis, diabetes, and chronic kidney disease. Human aortic smooth muscle cells (SMCs) undergo mineralization in response to elevated levels of inorganic phosphate (Pi) in an active and well-regulated process that involves increased activity of alkaline phosphatase and increased expression of core binding factor alpha-1 (Cbfa-1), a bone-specific transcription factor, with the subsequent induction of osteocalcin. Mounting evidence suggests an essential role for the heme oxygenase 1 (HO-1)/ferritin system to maintain homeostasis of vascular function. We examined whether induction of HO-1 and ferritin alters mineralization of SMCs provoked by high Pi. Upregulation of the HO-1/ferritin system inhibited HSMC calcification and osteoblastic differentiation. Of the products of the system, only ferritin and, to a lesser extent, biliverdin were responsible for the inhibition. We conclude that induction of the HO-1/ferritin system prevents Pi-mediated calcification and osteoblastic differentiation of SMCs mainly via the ferroxidase activity of ferritin. These findings prompted us to study the mechanism of iron induced bone defects. While iron overload and its association with osteoporosis has long been recognized, the pathogenesis and exact role of iron have been undefined. Osteoblast (OB) development and maturation are under the influence of Cbfa-1, which induces expression of OB-specific genes. We demonstrate that iron-provoked inhibition of OB activity is mediated by ferritin and its ferroxidase activity. We confirm this notion by using purified ferritin H-chain and ceruloplasmin, both known to possess ferroxidase activity that inhibited calcification, whereas a site-directed mutant of ferritin H-chain lacking ferroxidase activity failed to provide any inhibition. Furthermore, we report that such suppression is not restricted to inhibition of calcification, but OB-specific genes such as alkaline phosphatase, osteocalcin, and Cbfa-1 are all downregulated by ferritin in a dose-responsive manner. This study corroborates that iron decreases mineralization and demonstrates that this suppression is provided by iron-induced upregulation of ferritin and its ferroxidase activity.