Osteocalcin, or bone Gla protein, is a small protein secreted by osteoblasts that can undergo γ-carboxylation. The γ-carboxylated form binds hydroxyapatite and is abundant in bone extracellular matrix. In contrast, the undercarboxylated circulating form has been implicated as a novel hormone and positive regulator of glucose homeostasis. Importantly, osteocalcin expression has been described in calcifying vascular smooth muscle cells (VSMCs), although the physiological significance of this observation has remained unclear. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Idelevich et al1 show that osteocalcin is potentially a novel regulator of osteochondrogenic differentiation of pathologically mineralizing VSMCs. They reveal that osteocalcin, via hypoxia-inducible factor 1α signaling, stimulates expression of osteochondrogenic transcription factors in VSMCs, as well as a shift in cellular metabolism toward glycolysis. This study provides the first evidence that osteocalcin may be an active player in vascular calcification, with its presence in the calcified vasculature, and potentially the circulation, activating novel signaling pathways that promote mineralization. See accompanying article: Idelevich A, Rais Y, Monsonego-Ornan E. Bone Gla protein increases HIF-1α-dependent glucose metabolism and induces cartilage and vascular calcification. Arterioscler Thromb Vasc Biol . 2011;31:e55–e71. Pathological mineralization of the vasculature has a detrimental effect on cardiovascular function and is associated with increased mortality in patients with aging, atherosclerosis, type 2 diabetes, and chronic kidney disease.2 Vascular smooth muscle cells (VSMCs) orchestrate the mineralization process, which is mediated in part by their osteochondrocytic differentiation in the vessel wall. This phenotypic transition is characterized by expression of Runx2 and Sox9, master transcription factors that regulate bone and cartilage differentiation during developmental osteochondrogenesis, as well as other bone- and cartilage-specific proteins, many with undefined functions.3 One of these proteins, osteocalcin, is a small γ-carboxylated protein that is expressed by both osteoblasts and VSMCs and abundantly deposited …