A Novel Vascular Metabolic and Osteoinductive Factor?

Osteocalcin, or bone Gla protein, is a small protein secreted by osteoblasts that can undergo -carboxylation. The -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 1 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.