Objective-To assess the association of circulating bone marrow-derived osteo-progenitors with vascular calcification in mouse models and patients with peripheral artery disease.Methods-We estimated the percentage of circulating mononuclear cells expressing osteocalcin in 2 mouse models of aortic calcification developed in osteoprotegerin-deficient mice (OPG −/− ) using flow cytometry. Aortic calcification was assessed in mice principally by a bioassay of harvested aortas. In patients with peripheral artery disease osteocalcin-positive cells (estimated by flow cytometry) were related to aortic calcification volume assessed from computed tomography.Results-The amount of extractable aortic calcium was increased in both mouse models used in comparison to controls. The percentage of circulating mononuclear cells expressing osteocalcin was correlated to the amount of extractable aortic calcium in male (r=0.525, p=0.02) and female OPG −/− (r=0.564, p=0.02) mice and also in animals in which calcification was accelerated using calcitriol (r=0.64, p=0.01). Patients with more severe aortic calcification had a greater percentage of circulating OCN + MNCs (median 4.07 %, IQR 3.76-4.39, n=12) than those with less severe aortic calcification (median 3.10 %, IQR 2.32-3.60, n=11, p=0.05).Conclusions-This study demonstrates that aortic calcification can be robustly quantified in 2 mouse models. In these models and patients with peripheral artery disease circulating osteocalcin positive mononuclear cells are associated with the severity of aortic calcification.

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Background:To investigate the association between aortic calcification, concentrations of stem-cell-mobilizing cytokines and osteocalcin-positive mononuclear cells in a mouse model and patients with peripheral artery disease. Methods and Results:We estimated the concentration of the stem-cell-mobilizing cytokines stromal cellderived factor α (SDF-1α), granulocyte colony stimulating factor and stem cell factor in a mouse model of aortic calcification developed in osteoprotegerin-deficient (OPG -/-) mice, as well as in patient plasma samples. Calcification was estimated by a colorimetric assay of extracts of harvested mice aortas and by computed tomographic angiogram images in patients. The cytokine concentrations were assessed for association with the severity of calcification and the percentage of osteocalcin-positive mononuclear cells (OCN + MNC) using non-parametric analysis. The serum concentration of stromal SDF-1α and granulocyte-colony stimulating factor (G-CSF) were significantly greater in OPG -/-compared to control mice. The percentage of circulating OCN + MNC was correlated to the concentration of SDF-1α in OPG -/-mice. These cytokines also correlated with the severity of calcification in OPG -/-mice. Patients with more severe calcification had a higher plasma concentration of the cytokines than those with less marked aortic calcification. The concentrations also correlated with circulating OCN + MNC and aortic calcification volumes. Conclusions:The association between stem cell cytokines, OCN + MNC and calcification suggests a possible role of bone-derived osteoprogenitor cells in the pathogenesis of vascular calcification. (Circ J 2011; 75: 1227 -1234

This article reviews the association between bone and artery disease, with particular relevance to progenitor cells. The review was based on insight gained by analysis of previous publications and on-going work by the authors. A large number of studies have demonstrated a correlation between bone pathology, particularly osteoporosis, and atherosclerosis. In this review we highlight the particular aspect of bone marrow progenitor cells in the bone-artery link. Progenitor cells, primarily those believed to give rise to endothelial cells, have been inversely correlated with atherosclerosis severity and risk factors. Therapeutic approaches aimed at manipulating progenitor cells in revascularization and vascular repair have demonstrated some promising results. Subtypes of progenitor cells have also been linked with vascular pathology, however, and further studies are required to assess relative beneficial and pathologic effects of bone marrow-derived progenitors. Further understanding of the link between bone and artery pathophysiology is likely to be of significant value in developing new therapies for vascular disease.