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(Circulation. 1995;92:2029-2032.)
© 1995 American Heart Association, Inc.

Articles

A Skeleton in the Atherosclerosis Closet

Linda L. Demer, MD, PhD

From the University of California, Los Angeles.

Correspondence to Linda Demer, MD, PhD, University of California, Los Angeles, Department of Medicine, Division of Cardiology, Box 951679, Room 47-123, Center for the Health Sciences, Los Angeles, CA 90095-1679. E-mail ldemer.medicine.medsch.ucla.edu.

Key Words: atherosclerosis • calcium • cardiovascular diseases • osteopontin

	Introduction

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Routine chest x-rays often reveal calcium mineral deposits of the aorta and cardiac valves, sometimes with a density comparable to that of bone. Since atherosclerosis in the early 1900s was long dismissed as a passive, degenerative, inevitable process of aging, interest in its mechanism has been limited. Calcification in the coronary arteries has been widely regarded as uncommon. Recently, two new imaging methods, ultrafast computed tomography (UFCT) and intravascular ultrasound (IVUS), have changed this impression by revealing mineral deposits in the vast majority of significant lesions and in 90% of patients with coronary artery disease.^{1 2}

UFCT and IVUS studies showed the unexpected result that coronary calcification occurs in the absence of coronary narrowing. In the simplest terms, where there is coronary calcification, there is usually atherosclerosis, but not necessarily stenosis. Some take this to mean that calcification is not a useful marker because it does not diagnose coronary narrowing specifically. Another interpretation is that calcification is a useful marker of early coronary atherosclerosis, in that it occurs long before end-stage disease, during the stage of compensatory enlargement. If this is so—and it agrees with reports of calcification in very young patients with familial hypercholesterolemia³ —coronary calcification may turn out to be useful as a marker for early, not necessarily stenotic, atherosclerosis.

Contributing to the notion that calcification is uncommon is the absence of calcified lesions among textbook examples of vascular disease. One reason may be that early calcium deposits are washed out by routine histological preparation.⁴ In addition, selection bias may occur at several levels: harvesting calcified specimens dulls scalpel blades, sectioning calcified specimens without decalcification damages microtome blades, and fragmentation and strewing of the mineral across sections results in messy photomicrographs unsuitable for publication.

In this issue of Circulation, O'Brien and colleagues⁵ provide evidence that valvular as well as vascular calcification is an active, regulated process with similarities to bone mineralization. They demonstrate presence of the bone matrix protein osteopontin in extracellular matrix around calcium mineral deposits as well as in adjacent macrophages. Active synthesis of osteopontin by these macrophages but not by remote macrophages was shown by in situ hybridization.

	Recent History of Osteopontin in Vascular Calcification Research

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Osteopontin was first recognized as a molecule produced by osteoclasts to adhere to bone mineral during resorption. It is also produced by osteoblasts but at a lower level.⁶ Its name derives from the image of osteopontin as a bridge between osteoclasts and bone matrix. Osteopontin first came to the attention of vascular biologists when Giachelli and colleagues,⁷ using subtraction hybridization to compare two phenotypes of smooth muscle cells, identified a differentially expressed gene as encoding osteopontin. Knowing that bone matrix vesicles⁸ and full-fledged bone tissue can arise in atherosclerotic lesions, our research group hypothesized an analogy between vascular calcification and osteogenesis. Boström et al⁹ demonstrated expression of the osteogenic differentiation factor bone morphogenetic protein-2 (BMP-2) in calcified human plaques. Watson et al¹⁰ developed a novel in vitro model that allowed cloning of calcifying vascular cells derived from the artery wall that had the characteristic features of osteoblasts. Since then, a variety of bone matrix proteins have been identified in atherosclerotic lesions by several other groups.^{11 12 13 14 15} Osteopontin mRNA appears to be found predominantly in lesion monocyte/macrophages but also in smooth muscle cells.

	Absence of Media in Valve Leaflets

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
O'Brien et al⁵ made a clever choice in studying the aortic valve: The unique structure of valve leaflets, with two layers of intima sandwiching interstitial cells, has no tunica media. This circumstance allowed the authors to limit the number of different cell types that could be involved in the process. An implication is that medial smooth muscle cells are not essential for vascular calcification or for osteopontin synthesis.

	Macrophages or Osteoclasts?

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Although O'Brien and colleagues⁵ determined that the cells producing the osteopontin are CD68-positive, they may not necessarily be macrophages. Another intriguing possibility is that the osteopontin-producing cells are osteoclasts, which are also CD68-positive. The authors observed that only the subset of macrophages closest to calcium deposits were producing osteopontin, raising the question of phenotypic modulation or redifferentiation. Macrophage-to-osteoclast conversion has been demonstrated in other contexts,^{16 17} and bone matrix and calcium mineral fragments induce recruitment and differentiation of osteoclasts.^{18 19 20} Cells with all the histological features of osteoclasts have been described in atherosclerotic calcification.²¹

	Clinical Significance of Cardiovascular Calcification

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Calcification in the aorta and aortic valve adversely affects hemodynamics and most likely contributes to heart disease morbidity. Increased rigidity of either tissue creates simultaneous supply-side and demand-side coronary insufficiency because cardiac work is increased in the face of limited coronary supply. In the aortic valve, calcification directly impedes outflow and increases work. In the aorta, calcification prevents the normal stretch and recoil with each systolic impulse. Loss of aortic compliance increases cardiac work,²² and loss of recoil interferes with coronary perfusion. Normal aortic stretch during the systolic impulse, like the downstroke on a trampoline, stores energy in the elastin layers. The rebound during diastole normally provides the driving pressure for coronary flow, but it is lost when the aorta is rigid. These effects may contribute to hypertension, chronic angina, heart failure, and possibly syndrome X. Calcification increases solid shear stress in plaque,²³ increases rupture and dissection during balloon angioplasty,²⁴ and is associated with increased risk of myocardial infarction.²⁵ Since the increase in solid shear stress is due to the interface between soft and rigid tissue, which is where rupture occurs during angioplasty, it is conceivable that calcification is most hazardous when it is at an intermediate stage. Extensive circumferential mineralization may actually stabilize lesions, but at the same time, it must block compensatory enlargement, unless the mineralized tissue is also remodeled. An interesting hypothesis is that calcification status distinguishes between atherosclerotic lesions that cause long-standing, stable angina and those that cause acute myocardial infarction.

	Teleology

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Does cardiovascular calcification have any survival value? A unifying feature of all soft tissue calcification is chronic inflammation. Calcification (and eventually bone) forms around and surrounds foreign bodies, parasites, infections, and atherosclerosis. When a noxious focus resists the oxygen radical ammunition of immune and phagocytic cells, a strategy of isolation by walling it off with mineral has value. The mechanism by which cancer evades this defense is not known, but understanding it could lead to new treatments for both cancer and atherosclerotic calcification. Another interpretation is that calcification strengthens tissue under increased stress or weakens it by remodeling.²⁶ It is notable that bone calcification is exquisitely sensitive to mechanical stress. Osteopontin and calcification are also associated with transplanted valve tissues and with early breast cancer.

A minor note on terminology: some oppose using the term calcification in reference to calcium deposits, on the basis that calcification is defined as a process rather than a calcified structure. However, since Webster's recognizes both definitions, the common usage is employed here.

	Osteoid and Atherosclerotic Matrix

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Why invoke an analogy with bone calcification? It may be simpler to consider vascular calcification merely a result of minor modifications in artery wall processes—just "passive" crystallization mediated by osteopontin in a permissive matrix produced by phenotypically modulated artery wall cells. However, current concepts of bone calcification are essentially the same—passive crystallization mediated by osteopontin in a permissive matrix produced by osteoblasts. Calcium mineral is not secreted directly from cells; rather, it forms extracellularly in a matrix containing osteopontin, called osteoid. Osteoid generally undergoes mineralization about 10 days after secretion, at about 10 µm from the osteoblast. Two factors that permit crystallization at low ionic concentrations of calcium and phosphate are bone matrix proteins and matrix vesicles. Both are present in calcified valves²⁷ and atherosclerotic lesions. Atherosclerotic matrix includes not only osteopontin but also collagen I, matrix gla protein, osteonectin, osteocalcin, and matrix vesicles.^{8 14 28 29 30 31} From the point of view of bone biologists, these ingredients describe osteoid. Since much of atherosclerotic plaque consists of matrix and at least some of the matrix resembles osteoid, the early phases of osteogenesis could contribute directly to arterial narrowing. The analogy to bone is also supported by the occurrence of fully formed bone tissue in calcified human aortic valves.³² The possibility that calcium deposits without bone features are precursors of bone is strongly supported by the seamless contiguity observed by our group and described by early pathologists.

	Osteopontin in Solution

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
As noted by the authors, it is uncertain whether osteopontin has a positive or negative role in mineralization. One interpretation of the literature is that it may be capable of either, much as surgical forceps can either separate or appose tissues. In solution and in urine, where it is called uropontin, osteopontin inhibits mineralization.³³ It has been hypothesized that in a specific matrix environment, osteopontin undergoes a configurational change in its hairpin structure through which it enhances crystallization, possibly by apposing the ions.³⁴

	Osteoporosis Paradox

Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 
Vascular calcification often occurs in women with osteoporosis. This raises an important public health paradox: If calcium is accumulating in the arteries while leaking from the skeleton, can we assume that supplemental calcium goes selectively to bone? Considering the large number of postmenopausal women taking supplements, the possibility that they are increasing their risk of heart disease in an effort to prevent osteoporosis should have been questioned long ago. Adding to the complexity of this issue is the positive correlation between osteoporosis and vascular disease found in some studies.^{35 36} A mechanistic link has not been shown, but certain factors, such as parathyroid hormone, parathyroid hormone–related peptide, vitamin D, estrogen, and a variety of cytokines, influence both processes. Vitamin D has limited effects on osteoporosis when given at doses that only increase intestinal calcium uptake,³⁷ but when given at high doses in experimental animals, it produces vascular calcification.^{38 39} The direct effects of vitamin D are through response elements in genes for the bone matrix proteins, such as osteocalcin and osteopontin.⁴⁰ Exogenous vitamin D may even preferentially affect the vasculature, since it is carried in the blood by lipoproteins⁴¹ rather than on the vitamin D–binding protein that carries endogenous vitamin D. Thus, LDL may carry vitamin D into the artery wall along with its close relative cholesterol, and vitamin D may accumulate there to high concentrations. Calcium mineral is found to colocalize with cholesterol at the ultrastructural level in atherosclerotic plaque.⁴² Given the far greater risk of mortality from cardiovascular disease than from osteoporotic fracture, it is essential to determine whether calcium supplements aggravate cardiovascular calcification before recommendations for postmenopausal women are widely disseminated.

In 1863, Virchow⁴³ described cardiovascular calcification as "an ossification, not a mere calcification." A half century later, Bunting²¹ concluded that the mechanism is "a metaplasia of connective tissue cells into osteoblasts," with mature bone formation following angiogenesis and with hematopoietic marrow colonization following immigration of peripheral blood stem cells. They and students of vascular calcification in the 1950s and 1960s, such as Haust and More⁴⁴ and Pollack,⁴⁵ predicted from histopathologic observation alone that vascular calcification was an important aspect of atherosclerosis similar to bone. Studies at the cellular and molecular levels now support earlier predictions of a molecular and genetic basis.^{46 47} It is ironic that studies of embryonic osteogenesis should contribute to understanding the cause and potentially the prevention of a disorder once attributed to aging.

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Top Introduction Recent History of Osteopontin... Absence of Media in... Macrophages or Osteoclasts? Clinical Significance of... Teleology Osteoid and Atherosclerotic... Osteopontin in Solution Osteoporosis Paradox References

 

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				K. Graf, Y. S. Do, N. Ashizawa, W. P. Meehan, C. M. Giachelli, C. C. Marboe, E. Fleck, and W. A. Hsueh Myocardial Osteopontin Expression Is Associated With Left Ventricular Hypertrophy Circulation, November 4, 1997; 96(9): 3063 - 3071. [Abstract] [Full Text]

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