Bone Sialoprotein and the Paradox of Angiogenesis Versus Atherosclerosis

Abstract

Bone sialoprotein (BSP) is a protein thought to be highly specific for bone. BSP contains an arginine-glycineaspartic acid (RGD) cell attachment sequence involved in osteoclast adhesion to bone matrix via the vitronectin receptor and plays an important role in the early process of bone mineralization and resorption. The study by Bellahcène et al 1 in this issue of Circulation Research indicates that BSP mediates adhesion and chemotactic migration of endothelial cells and promotes angiogenesis, suggesting that BSP may be an important factor in angiogenesis and the initiation of atherosclerosis, two processes that are probably related.In earlier studies, Folkman 2 hypothesized that tumor growth beyond a few millimeters requires recruitment and growth of a new microcirculation, or angiogenesis, which is induced by tumors as lifelines for oxygen and nutrients. New blood vessels also provide exits for cancer cells to spread to other parts of the body. Angiogenesis is also involved in physiological conditions, such as embryogenesis, and other pathological conditions, such as wound healing. The process of angiogenesis requires a highly coordinated series of events, including endothelial cell proliferation, migration, tube and lumen formation, and, in some cases, recruitment of smooth muscle cells (SMCs) and other adventitial cells.Adhesive interaction of cells with components of the extracellular matrix is a recognized requirement for cell proliferation and migration. Evidence indicates that many of the adhesive interactions are mediated by members of the integrin family of heterodimeric adhesion receptors. Among these integrins, ␣ v ␤ 3 , which is expressed by a variety of cell types, has been shown to play a key role in the cell migration involved in metastasis and angiogenesis. 3 The work presented by Bellahcène et al 1 indicates that BSP, a bone-associated protein that contains the RGD sequence, a common recognition sequence for most integrins, binds ␣ v ␤ 3 in endothelial cells and mediates the migration of such cells, extending the study by Byzova et al. 4 Furthermore, Bellahcène et al 1 show that another integrin, ␣ v ␤ 5 , does not bind BSP, suggesting that there is a certain degree of specificity for the interaction between BSP and ␣ v ␤ 3 .The in vivo data indicating that BSP promotes angiogenesis via its interaction with ␣ v ␤ 3 integrin and that such an angiogenic effect is probably even greater than that of basic fibroblast growth factor (bFGF) 1 are intriguing. These data underscore the physiological and pathophysiological consequences of the interaction between BSP and ␣ v ␤ 3 integrin and define BSP as a novel angiogenic factor. These findings may provide an explanation for the previously established association of BSP expression levels in tumors with the development of bone metastases. 5 Higher BSP expression in the tumor correlates with an increased risk of metastasis of carcinomas to bone tissue, which could be due to angiogenesis enhancement by BSP. In addition, BSP expression in the tumor may facil...

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