Bone Gla Protein Increases HIF-1α–Dependent Glucose Metabolism and Induces Cartilage and Vascular Calcification

Abstract

Objective-Bone

Plasma osteocalcin levels as a predictor of cardiovascular disease in older men and women: a population-based cohort study

“…Elevated OC levels have been shown to be associated with osteoporosis (2). OC is also expressed in calcified atherosclerotic lesions, where it is believed to be a mediator in the calcification process (1,3,4,5). Vascular calcification appears to be adipocytes to regulate insulin secretion and sensitivity and fat mass (7,8).…”

From Skeleton to Cytoskeleton

“…A recent study points out that osteocalcin stimulates cartilage and vascular calcification in rats through the hypoxia-inducible factor 1␣-dependent mechanism on glycolytic breakdown of glucose. 48 The sources of such osteoblast-like cells remain unclear; therefore, the identification of osteocalcin in human intimal lesion has several important implications about its origin. First, active osteogenesis by osteoblast-like cells is demonstrated in the early stage of inflamed atherosclerotic aortae.…”

Osteocalcin

“…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 al 1 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.…”

“…9,10 Importantly, in the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Idelevich et al present data revealing a novel function for osteocalcin in both cartilage and the vasculature and show that osteocalcin fuels glucose utilization by VSMCs and promotes their osteochondrogenic differentiation ( Figure). 1 Idelevich et al used vitamin D treatment of rats to induce mineralization of the vasculature. They demonstrated that osteocalcin mRNA was upregulated concomitantly with the onset of VSMC osteochondrocytic differentiation and that the protein accumulated in the calcified vessel wall.…”

“…15 Finally, further interrogation of the mechanisms of vascular calcification in response to osteocalcin and HIF-1␣ needs to be performed. Although it is clear that in the study by Idelevich et al, 1 HIF-1␣ signaling was promoting both metabolic changes and osteochondrocytic differentiation, whether the metabolic changes were required for osteochondrocytic differentiation was never directly tested. Indeed, these changes were induced by osteocalcin at very different rates: minutes for the metabolic changes in experiments with recombinant osteocalcin compared with 7 to 21 days for osteochondrogenic differentiation.…”