doi: 10.1161/01.RES.0000219673.71778.df
© 2006 American Heart Association, Inc.
Editorials |
Pitting Phosphate Transport Inhibitors Against Vascular Calcification
From the Departments of Medicine, Physiology, and Biomedical Engineering, The David Geffen School of Medicine at UCLA.
Correspondence to Linda L. Demer, MD, PhD, Department of Medicine, BH-307 Center for Health Sciences, 10833 LeConte Avenue, Los Angeles, CA 90095-1679. E-mail Ldemer{at}mednet.ucla.edu
See related article, pages 905–912
Key Words: vascular • calcification • Pit-1 • mineralization • phosphate transport
Vascular calcification is widespread in patients with coronary artery disease, peripheral vascular disease, and diabetes, but by far the most severe and extensive vascular calcification is in those with end-stage renal disease, especially those with the longest exposure to hemodialysis. Their coronary calcification scores on electron beam CT scanning are often an order of magnitude greater than in ordinary CAD patients. The severity of their vascular calcification closely relates to the duration of hemodialysis; after a decade of dialysis, even pediatric patients are affected.1 Histopathologically, these calcium deposits are located primarily in the medial layer, unlike atherosclerotic calcification, which is located within the intimal lesions. This and other differences suggest that the two forms may have different underlying mechanisms. Although it remains controversial whether vascular calcification promotes plaque destabilization, it is clear that arterial rigidity contributes to hypertension, cardiac hypertrophy, and heart failure, in part because of increased aortic impedance, as seen in experimental models that use aortic banding to produce heart failure. This is likely the reason that patients with chronic renal disease most often die of cardiovascular complications.
This clinical phenomenon offers important mechanistic clues about vascular calcification, as recognized by Giachelli and colleagues at University of Washington. As a result of their interdisciplinary work, they were aware that bone biologists routinely treat their osteoblast cultures with phosphate supplements, usually in the form of beta-glycerophosphate, and that phosphate supplements accelerated osteoblast mineralization. Together with the knowledge that end-stage renal disease patients almost uniformly have both elevated serum phosphate and extensive vascular calcification, this observation raised the possibility that hyperphosphatemia may be a major contributing factor to the calcification in these patients. These investigators went on to show that phosphate supplements also accelerate mineralization in vascular cells and implicated sodium-dependent phosphate transport.2 In this issue of Circulation Research, these investigators3 now provide compelling evidence that a specific phosphate transporter is essential for in vitro vascular calcification and, possibly, the severe mineralization of the vascular tree in end-stage renal disease patients.
As recently as the 1990’s, vascular calcification was dismissed as a passive, degenerative, inevitable process of aging. It is now generally recognized that the process is governed through both positive and negative regulatory mechanisms at molecular and cellular levels.4–7 That the process is attributable to biological processes rather than chemical degeneration is evidenced by the centuries-old observation that calcified atherosclerotic lesions often contain bone tissue, including trabeculae, osteocytic lacunae, marrow elements, and the architecture of woven bone. Early evidence for molecular genetic regulation of vascular calcification came from the matrix GLA protein (MGP)–deficient mouse, which was unexpectedly found to develop complete aortic ossification.8 Other genetic abnormalities also feature vascular calcification as a phenotype, including deficiencies of osteoprotegerin, fibrillin, and NPP1, the enzyme that produces pyrophosphate, an alkaline phosphatase inhibitor.
In the past decade, a large number of regulatory mechanisms for vascular calcification have been proposed (Table). Though not all the factors listed have been definitely linked to vascular calcification, some evidence has been reported at the level of in vitro, in vivo, or clinical studies, for each. Many of these regulators may not act directly on calcium phosphate crystal generation, but instead act on upstream processes, such as osteogenic differentiation. For example, although the OPG-deficient mouse develops aortic calcification, it is not clear whether OPG directly inhibits mineral formation. More likely, according to emerging data, OPG acts indirectly, by diverting ligands known to promote calcification.9 Many of these regulators act in concert. For example, alkaline phosphatase, which appears to function by providing phosphate ions for mineral formation, is inhibited by inorganic pyrophosphate, which, in turn, is generated by nucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Recently, Terkeltaub and colleagues have shown endochondral calcification in aortas of mice deficient in NPP1,10 the human disease correlate of which is a fatal congenital disorder, idiopathic infantile arterial calcification.11 Other networking has been observed between factors regulating vascular mineralization: matrix GLA protein blocks activity of bone morphogenetic protein-2, warfarin blocks posttranslational modifications that are essential for MGP function, and BMP-2, Msx-2, and Wnt regulate one another and are inhibited by PTH.12–14 These interactions make it difficult to pinpoint any individual molecule(s) as the principal factor(s) in vascular calcification in general. They also likely account for the findings that the serum levels of molecules that inhibit vascular cell calcification in vitro, such as MGP and OPG, actually associate positively with vascular calcification in humans.15,16
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For vascular calcification in renal patients, it becomes even more challenging to single out culprits, because these patients both spontaneously develop metabolic abnormalities that affect mineralization, and they also receive routine treatments with agents that affect mineralization. Patients with chronic renal disease who develop high serum phosphorus levels are typically placed on dietary phosphate restriction or phosphate binders, some of which include calcium. Patients with chronic renal disease are also treated with the active form of vitamin D3 (calcitriol) because their kidneys lack the capacity to convert precursor molecules to the functional hormone. It has been known for decades that high oral doses of calcitriol and other forms of vitamin D reliably induce vascular calcification in animals; in fact, hypervitaminosis D is used widely as an experimental model for vascular calcification17 As noted earlier, high serum phosphate is typical in these patients, and this triggers secondary hyperparathyroidism, with high serum PTH. To add to the complexity, recent evidence suggests that calcitriol may ameliorate secondary hyperparathyroidism in a rat model.18 Those end-stage renal disease patients who depend on hemodialysis often have arteriovenous shunts created surgically in their arm vessels for convenient catheter access. To prevent thrombosis at these sites, the patients receive anticoagulant therapy with warfarin, which prevents vitamin K–mediated gamma-carboxylation of glutamate residues necessary for MGP function, thus potentially disabling an inhibitor of vascular calcification. It has been suggested that warfarin may increase vascular calcification even in patients without renal disease.19 Patients with chronic renal disease are also at high risk of developing calcemic uremic arteriolopathy, a devastating disease of microvascular calcification often leading to necrosis and amputation. It is possible that this process involves osteogenic differentiation of microvascular pericytes, which has been demonstrated in vitro and in vivo by Canfield’s group.5 Clearly, these considerations offer challenges in understanding and addressing the problem of vascular calcification in renal disease.
In the present report, Li et al provide compelling data that the type III sodium-dependent phosphate cotransporter, Pit-1, has a direct role in vascular calcification.3 This group previously found that Pit-1 induces osteogenic differentiation, as indicated by expression of the osteogenic master regulatory factor, core binding factor a-1 (Cbfa-1), as well as downstream differentiation markers such as osteopontin.2 Now, using Pit-1 small interfering double-stranded RNA expressed via retroviral methods in SMC, they decreased phosphate transport activity and demonstrated reduced phosphate-induced SMC calcification, which was rescued by overexpression of Pit-1. Their findings introduce the exciting possibility that phosphate transport inhibitors may function similarly in vivo.
Given that Pit-1 controls mineralization at the level of an upstream regulator of differentiation, it is interesting that the medial calcification of renal disease patients has fewer characteristics of osteogenic tissue than atherosclerotic calcification. One possible explanation is that the osteogenic features require angiogenesis, which is driven by factors in atherosclerotic plaque. In addition, atherosclerotic calcification may involve other pathways, such as Msx-2–regulated Wnt/beta-catenin signaling. Towler and colleagues have shown that this pathway controls differentiation through a different upstream regulator of differentiation, Osterix, which favors the cartilaginous lineage.20
Overall, the work by Li et al and the research in this field are examples of the rapid advances that are possible with interdisciplinary communication, combining observations from nephrology, bone biology, and vascular biology. Clinical nephrologists and hemodialysis specialists are already modifying clinical management in recognition of the link between phosphate and vascular calcification.
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Acknowledgments |
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The authors receive support from grants from the National Institutes of Health (HL/AR69261) and the American Heart Association (GIA 0555028Y).
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Related Article:
- Role of the Sodium-Dependent Phosphate Cotransporter, Pit-1, in Vascular Smooth Muscle Cell Calcification
- Xianwu Li, Hsueh-Ying Yang, and Cecilia M. Giachelli
Circ. Res. 2006 98: 905-912.[Abstract] [Full Text] [PDF]
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