A Paracrine Regulator of Vascular Calcification and Smooth Muscle Phenotype

Cellular and molecular similarities between orthotopic versus heterotopic mineral deposition are beginning to emerge. During bone formation, the major orthotopic venue, two general mechanisms drive tissue mineralization1 (Table). With endochondral ossification, an avascular cartilaginous skeletal template is first established by chondrocytes; this cartilage template calcifies and is subsequently resorbed and replaced by bone through osteoblast-mediated synthetic activity.1 With intramembranous ossification, osteoblast-mediated bone formation occurs directly in a type I collagen-based extracellular matrix, without preceding cartilage template formation.1 During vascular calcification, the major heterotopic venue, ossification mechanisms similar to those mediating bone formation contribute to vascular calcium load.2,3 At least 4 distinct histoanatomic variants of vascular calcification can be readily identified2,3 (Table). Eccentric lumen-deforming atherosclerotic calcification is associated with both osteogenic and chondrogenic gene regulatory programs in areas overlapping and adjacent to calcifying necrotic fibro-fatty plaques.4 With evolution to advanced disease, endochondral bone formation is observed.2,5 Medial artery calcification, by contrast, is a concentric mural calcification process reminiscent of matrix vesicle-mediated intramembranous bone formation (Table).2,3 In cardiac valve calcification, valve thickening, stippled calcification, and degenerative fatty expansion in the valvular fibrosus occurs early on; this is associated with monocyticand T-cell infiltration6 and the elaboration of osteogenic gene expression.7 Finally, in the setting of an elevated calcium phosphate product, vascular tissue calciphylaxis occurs in concert with widespread soft tissue calcification, without requisite recruitment of active osteogenic or chondrogenic processes.8 Once considered benign, the deleterious clinical consequences of vascular calcification have now become clear.9,10