Osteopontin. Between a rock and a hard plaque.

Vascular calcification is widely regarded as merely a rare, end-stage, passive, degenerative, and inevitable process of aging. Decades ago, atherosclerosis had been similarly dismissed, but extensive research finally demonstrated its active regulation. Current research is now revising outdated views of vascular calcification. New imaging techniques made it clear that coronary calcification is neither rare nor end stage but occurs in 90% of patients with coronary artery disease1 and that the vast majority of significant coronary stenoses are calcified.2 Coronary calcification is also associated with increased cardiovascular risk.3,4 One clue to the regenerative—rather than degenerative— nature of vascular calcification is that it often includes histopathological features of bone. In the 1700s, Morgagni and others described arterial ossification in their postmortem examinations: “. . . the left coronary artery appeared to have been changed into a bony canal from its very origin. . . . ”5 In 1863, Virchow labeled the vascular changes as “ossification, not mere calcification, occurring by the same mechanism by which an osteophyte forms on the surface of bone.”6 In 1906, marrow was described within the bone tissue within the arteries—a richly vascularized cellular red marrow containing adipocytes, neutrophils, eosinophils, lymphoid and erythroid cells, reticulocytes, megakaryocytes, and other characteristic elements of marrow.7 Bunting further described (and we have also observed) evidence of resorption by osteoclastlike cells in this tissue. Within the vascular tree, the aorta and cardiac valves are the most common sites of ossification, and these contain all the stages of osteogenesis from the youngest variety of osteoid tissue up to true bone.8 Calcification of cardiac valves also involves lipid deposition and expression of bone matrix proteins.9 Because of various selection bias effects, the ossified form of vascular calcification may be more common than currently believed.10 One pathologist argued that the ossified lesion “is regarded as rare, chiefly because it is not more often searched for.”7 The concept that vascular calcification is living tissue undergoing active remodeling suggests that it could be reversed through biological manipulations, in effect, producing osteoporosis locally in the artery wall. In this issue of Circulation Research, Wada et al11 elucidate one of the mechanisms governing vascular calcification that may lead to a therapeutic approach. Using ultrastructural localization and dynamic measurement of mineral deposition, the authors provide strong evidence for the role of the bone matrix protein osteopontin in inhibition of vascular calcification. This dose-dependent inhibition was shown to be most likely due to direct association of osteopontin with growing apatite crystals. Osteopontin (OPN), an acidic phosphorylated glycoprotein, was named for its function as a bridge between cells and mineral. Forming a proteinaceous coating over the solid crystal surface, OPN mediates attachment of both osteoblasts and osteoclasts to bone mineral through interaction of its highly conserved GRGDS sequence with integrins.12 In cell-free solutions and gels, OPN inhibits apatite crystal formation.13 For this reason, OPN, which is present in urine and other body fluids, is believed to prevent stone formation. Other bone matrix proteins also inhibit mineralization by blocking growth or delaying nucleation14 and some, such as bone sialoprotein, initiate crystal nucleation. Many of these are also expressed in the artery wall or in atherosclerotic lesions. Osteocalcin (bone gla protein) binds to apatite and is believed to inhibit crystal formation based on in vitro studies and a genetically modified mouse model.15,16 When gamma carboxylated at glutamic acid residues by a vitamin K–dependent carboxylase, osteocalcin binds avidly to bone mineral. A related protein, matrix gla protein (MGP), which contains 5 gamma-carboxyglutamic acid (gla) residues, is also believed to inhibit mineralization, based on a mouse model described later. Some uncertainty remains concerning the function of bone matrix proteins, in that their behavior in cell-free solution or in gel-agarose medium may differ from that in a complex, fibrillar intercellular matrix in which proteins may undergo function-altering configurational changes. The purpose of several proteins, all with the same function—binding to and inhibiting growth of hydroxyapatite mineral—is unclear. One possibility is that the different lattice geometries on the different faces of the mineral crystal have different binding avidity for the different matrix proteins. This geometric selectivity would permit independent control of growth along each of the crystal axes. Thus, genetic regulation of the relative abundance of the various matrix proteins would actually govern crystal shape. Paradoxically, bone matrix proteins that inhibit apatite formation are found at increased levels in calcified human atherosclerotic plaque and in culture.17,18 One might expect that reduced levels of these factors would be necessary to permit mineralization. One possible explanation is that the inhibitory factors are induced in response to mineralization The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Medicine and Physiology, UCLA School of Medicine, Los Angeles, Calif. Correspondence to Linda L. Demer, MD, PhD, 47-123 CHS, UCLA School of Medicine, Los Angeles, CA 90095-1679. (Circ Res. 1999;84:250-252.) © 1999 American Heart Association, Inc.