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动脉硬化血栓血管生物学 2005年第7期
From the Departments of Medicine (L.L.D., Y.T.), Physiology (L.L.D.), and Bioengineering (L.L.D.), The David Geffen School of Medicine at UCLA.
Correspondence to Linda L. Demer, MD, PhD, Division of Cardiology, UCLA School of Medicine, Box 951679, Los Angeles, CA 90095-1679. E-mail LDemer@mednet.ucla.edu
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Rattazzi and colleagues demonstrate definitively that true cartilage and calcified cartilage tissue develop in the artery wall of the apoE (–/–) mouse.1 This key observation of neocartilage in a hyperlipidemic mouse provides strong support for the existence and function of vascular stem cells, and raises important questions about the origin of cells that produce ectopic tissue and the regulatory mechanisms determining their lineage identity.
See page 1420
The origin of ectopic vascular tissue remains unknown. Some possibilities include transdifferentiation of mature smooth muscle cells, initial differentiation of immature cells, and/or dedifferentiation of mature cells followed by redifferentiation. It is not known whether the cells arise from the artery wall, perhaps as embryonic remnants, or migrate from the circulation, after release from another tissue, such as the marrow stroma. The spectrum of lineages represented in vascular ectopic tissue is similar to that of marrow stromal cells and mesenchymal stem cells, suggesting that ectopic tissue is a manifestation of adult mesenchymal stem cells. In the past year, 3 groups independently demonstrated multilineage potential in adult vascular cells in vitro and in vivo, including chondrogenic, osteogenic, leiomyogenic, and, in some cases, adipogenic lineages.2–4 The repertoire of lineages of cells, which is similar to that of marrow stromal cells, and their capacity for self-renewal suggests that they are mesenchymal stem cells. Thus, the neocartilage found in this mouse model may represent aberrant differentiation of mesenchymal stem cells residing in the artery wall.
In humans, most ectopic tissue in atherosclerotic lesions is osteogenic,5 whereas in mice, the dominant lineage is chondrogenic.1,6 The cause of this distinction is not known. One consideration is the vasa vasorum. Because endochondral osteogenesis requires angiogenic invasion of a calcified matrix, the lack of vasa vasorum in mice may favor arrest of endochondral ossification at the stage of avascular cartilage. Another intriguing consideration is that bone morphogenetic protein-2, which can produce ectopic bone when injected into adult connective tissue, appears to regulate lineage acquisition in a dose-dependent manner. From highest to lowest concentrations, BMP-2 induces chondrogenic, osteogenic, and smooth muscle or adipogenic differentiation in mouse embryonic mesenchymal cells.7 Thus, if murine lesions have higher levels of BMP-2 or lower levels of its inhibitors, chordin, noggin or matrix GLA protein, then chondrogenesis may dominate. Thus, the nature of ectopic tissue produced may be determined by the relative activity of morphogens.
The list of factors that regulate osteogenic differentiation of vascular cells is rapidly growing. A partial list includes: osteopontin, bone morphogenetic proteins, Msx-2, certain oxidized lipoproteins and isoprostanes, sodium phosphate cotransporters, RANKL, PTH, matrix GLA protein, fibrillin, pyrophosphate and enzymes producing it, bisphosphonates, tumor necrosis factor-alpha, oxysterols, osteoprotegerin, insulin-like growth factor, high density lipoprotein, interleukins, 1,25-dihydroxyvitamin D, transforming growth factor-beta, estradiol, decorin, fetuin, and many others. As demonstrated by Towler and colleagues, Msx-2, lipoprotein receptor related protein-5/6, and the Wnt/?-catenin family are key downstream regulators of this process.8
An obvious culprit trigger in the apoE(–/–) mouse is its severe hyperlipidemia. Several lines of evidence support a role for oxidized lipids/lipoproteins in vascular calcification. Consistent with this, other mouse models of hyperlipidemia, C57Bl/6 and ldlr(–/–) mice, also develop vascular calcification when treated with a high-fat diet. The fact that the apoE(–/–) mice do not require a high- fat diet may reflect the severity of their hyperlipidemia, which, on a chow diet, is comparable to that of ldlr(–/–) mice on the high-fat diet.
In bone, atherogenic lipids and lipoproteins have a reciprocal effect on osteoblasts, inhibiting in vitro differentiation and mineralization, leading to the speculation that atherogenic lipids could promote both vascular calcification and osteoporosis. Consistent with this, the C57Bl/6 mouse, which is particularly vulnerable to the atherogenic effects of oxidized lipids, has unusually low bone density. Conversely, the C3H/HeJ mouse, which has a nonfunctional Toll receptor and is resistant to atherogenic stimuli, has a relatively high bone density. Furthermore, mice deficient in 12/15-lipoxygenase also have increased bone mineral density.9 These findings are consistent with the concept that atherogenic lipids reciprocally regulate vascular and bone mineralization through effects of inflammatory factors such as oxidized lipoproteins on osteogenic differentiation and mineralization.
However, Schilling et al recently reported that the apoE(–/–) mouse has increased bone mineral density, and the mechanism they propose has important implications for vascular calcification.10 They suggest that osteoblasts depend on absorption of fat-soluble vitamin K for the vitamin K-dependent -carboxylation of osteocalcin, a posttranslational modification required for its full function in regulating and limiting hydroxyapatite crystal formation. Thus, apoE deficiency would reduce lipoprotein-mediated uptake of vitamin K, blocking posttranslational modification and function of osteocalcin, ultimately allowing increased mineralization.
If osteoblastic cells indeed depend on apoE for uptake of fat-soluble vitamins, then apoE-deficient osteoblasts may lack another fat soluble vitamin, 1,25 dihydroxyvitamin D, which also regulates biomineralization. The potential impact of reduced availability of active vitamin D, cholecalciferol, which affects both osteoblastic and osteoclastic function, in apoE(–/–) mice is an interesting issue for the bone biologists.
The issue for the vascular biologists is that the artery wall also contains another protein that depends on a vitamin K-dependent -carboxylase for optimal function, matrix GLA protein (MGP).11,12 MGP is now believed to have a major role in inhibiting calcification in vascular cells, based on the dramatic phenotype of aortic ossification in the MGP-deficient mouse, and based on its ability to bind and inhibit BMP-213,14 which is also in the artery wall, as well as its potential to directly bind and block growth of hydroxyapatite crystals. To further complicate issues, vitamin D, which may also have limited uptake in the apoE null mouse, also regulates vascular calcification.15
Thus, it is conceivable that vascular calcification in apoE(–/–) mice is attributable to abnormal growth and differentiation of resident mesenchymal stem cells, in response to 2 factors: atherogenic lipids and unopposed activity of BMP due to undercarboxylation of MGP. In human atherosclerosis, there may be less effect on vitamin K and hence BMP activity, yielding osteogenic, rather than chondrogenic, ectopia.
References
Rattazzi M, Bennett BJ, Bea F, Kirk EA, Ricks JL, Speer M, Schwartz SM, Giachelli CM, Rosenfeld ME Calcification of advanced atherosclerotic lesions in the innominate arteries of apoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler Thromb Vasc Biol. 2005; 25: 1420–1426.
Cheng SL, Shao JS, Charlton-Kachigian N, Loewy AP, Towler DA. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J Biol Chem. 2003; 278: 45969–45977.
Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Bostrom K, Demer LL. Multilineage potential of cells from the artery wall. Circulation. 2003; 108: 2505–2510.
Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation. 2004; 110: 2226–2232.
Hunt JL, Fairman R, Mitchell ME, Carpenter JP, Golden M, Khalapyan T, Wolfe M, Neschis D, Milner R, Scoll B, Cusack A, Mohler ER3rd. Bone formation in carotid plaques: a clinicopathological study. Stroke. 2002; 33: 1214–1219.
Qiao JH, Fishbein MC, Demer LL, Lusis AJ. Genetic determination of cartilaginous metaplasia in mouse aorta. Arterioscler Thromb Vasc Biol. 1995; 15: 2265–2272.
Ahrens M, Ankenbauer T, Schroder D, Hollnagel A, Mayer H, Gross G. Expression of human bone morphogenetic proteins-2 or -4 in murine mesenchymal progenitor C3H10T1/2 cells induces differentiation into distinct mesenchymal cell lineages. DNA Cell Biol. 1993; 12: 871–880.
Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005; 115: 1210–1220.
Klein RF, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos AS, Shea M, Waters RV, Belknap JK, Peltz G, Orwoll ES. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science. 2004; 303: 229–232.
Schilling AF, Schinke T, Munch C, Gebauer M, Niemeier A, Priemel M, Streichert T, Rueger JM, Amling M. Increased bone formation in mice lacking apolipoprotein E. J Bone Miner Res. 2005; 20: 274–282.
Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL. Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol. 1998; 18: 379–388.
Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998; 18: 1400–1407.
Bostrom K, Tsao D, Shen S, Wang Y, Demer LL. Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem. 2001; 276: 14044–14052.
Wallin R, Cain D, Hutson SM, Sane DC, Loeser R. Modulation of the binding of matrix Gla protein (MGP) to bone morphogenetic protein-2 (BMP-2). Thromb Haemost. 2000; 84: 1039–1044.
Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000; 20: 317–327.(Linda L. Demer; Yin Tintu)
Correspondence to Linda L. Demer, MD, PhD, Division of Cardiology, UCLA School of Medicine, Box 951679, Los Angeles, CA 90095-1679. E-mail LDemer@mednet.ucla.edu
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Rattazzi and colleagues demonstrate definitively that true cartilage and calcified cartilage tissue develop in the artery wall of the apoE (–/–) mouse.1 This key observation of neocartilage in a hyperlipidemic mouse provides strong support for the existence and function of vascular stem cells, and raises important questions about the origin of cells that produce ectopic tissue and the regulatory mechanisms determining their lineage identity.
See page 1420
The origin of ectopic vascular tissue remains unknown. Some possibilities include transdifferentiation of mature smooth muscle cells, initial differentiation of immature cells, and/or dedifferentiation of mature cells followed by redifferentiation. It is not known whether the cells arise from the artery wall, perhaps as embryonic remnants, or migrate from the circulation, after release from another tissue, such as the marrow stroma. The spectrum of lineages represented in vascular ectopic tissue is similar to that of marrow stromal cells and mesenchymal stem cells, suggesting that ectopic tissue is a manifestation of adult mesenchymal stem cells. In the past year, 3 groups independently demonstrated multilineage potential in adult vascular cells in vitro and in vivo, including chondrogenic, osteogenic, leiomyogenic, and, in some cases, adipogenic lineages.2–4 The repertoire of lineages of cells, which is similar to that of marrow stromal cells, and their capacity for self-renewal suggests that they are mesenchymal stem cells. Thus, the neocartilage found in this mouse model may represent aberrant differentiation of mesenchymal stem cells residing in the artery wall.
In humans, most ectopic tissue in atherosclerotic lesions is osteogenic,5 whereas in mice, the dominant lineage is chondrogenic.1,6 The cause of this distinction is not known. One consideration is the vasa vasorum. Because endochondral osteogenesis requires angiogenic invasion of a calcified matrix, the lack of vasa vasorum in mice may favor arrest of endochondral ossification at the stage of avascular cartilage. Another intriguing consideration is that bone morphogenetic protein-2, which can produce ectopic bone when injected into adult connective tissue, appears to regulate lineage acquisition in a dose-dependent manner. From highest to lowest concentrations, BMP-2 induces chondrogenic, osteogenic, and smooth muscle or adipogenic differentiation in mouse embryonic mesenchymal cells.7 Thus, if murine lesions have higher levels of BMP-2 or lower levels of its inhibitors, chordin, noggin or matrix GLA protein, then chondrogenesis may dominate. Thus, the nature of ectopic tissue produced may be determined by the relative activity of morphogens.
The list of factors that regulate osteogenic differentiation of vascular cells is rapidly growing. A partial list includes: osteopontin, bone morphogenetic proteins, Msx-2, certain oxidized lipoproteins and isoprostanes, sodium phosphate cotransporters, RANKL, PTH, matrix GLA protein, fibrillin, pyrophosphate and enzymes producing it, bisphosphonates, tumor necrosis factor-alpha, oxysterols, osteoprotegerin, insulin-like growth factor, high density lipoprotein, interleukins, 1,25-dihydroxyvitamin D, transforming growth factor-beta, estradiol, decorin, fetuin, and many others. As demonstrated by Towler and colleagues, Msx-2, lipoprotein receptor related protein-5/6, and the Wnt/?-catenin family are key downstream regulators of this process.8
An obvious culprit trigger in the apoE(–/–) mouse is its severe hyperlipidemia. Several lines of evidence support a role for oxidized lipids/lipoproteins in vascular calcification. Consistent with this, other mouse models of hyperlipidemia, C57Bl/6 and ldlr(–/–) mice, also develop vascular calcification when treated with a high-fat diet. The fact that the apoE(–/–) mice do not require a high- fat diet may reflect the severity of their hyperlipidemia, which, on a chow diet, is comparable to that of ldlr(–/–) mice on the high-fat diet.
In bone, atherogenic lipids and lipoproteins have a reciprocal effect on osteoblasts, inhibiting in vitro differentiation and mineralization, leading to the speculation that atherogenic lipids could promote both vascular calcification and osteoporosis. Consistent with this, the C57Bl/6 mouse, which is particularly vulnerable to the atherogenic effects of oxidized lipids, has unusually low bone density. Conversely, the C3H/HeJ mouse, which has a nonfunctional Toll receptor and is resistant to atherogenic stimuli, has a relatively high bone density. Furthermore, mice deficient in 12/15-lipoxygenase also have increased bone mineral density.9 These findings are consistent with the concept that atherogenic lipids reciprocally regulate vascular and bone mineralization through effects of inflammatory factors such as oxidized lipoproteins on osteogenic differentiation and mineralization.
However, Schilling et al recently reported that the apoE(–/–) mouse has increased bone mineral density, and the mechanism they propose has important implications for vascular calcification.10 They suggest that osteoblasts depend on absorption of fat-soluble vitamin K for the vitamin K-dependent -carboxylation of osteocalcin, a posttranslational modification required for its full function in regulating and limiting hydroxyapatite crystal formation. Thus, apoE deficiency would reduce lipoprotein-mediated uptake of vitamin K, blocking posttranslational modification and function of osteocalcin, ultimately allowing increased mineralization.
If osteoblastic cells indeed depend on apoE for uptake of fat-soluble vitamins, then apoE-deficient osteoblasts may lack another fat soluble vitamin, 1,25 dihydroxyvitamin D, which also regulates biomineralization. The potential impact of reduced availability of active vitamin D, cholecalciferol, which affects both osteoblastic and osteoclastic function, in apoE(–/–) mice is an interesting issue for the bone biologists.
The issue for the vascular biologists is that the artery wall also contains another protein that depends on a vitamin K-dependent -carboxylase for optimal function, matrix GLA protein (MGP).11,12 MGP is now believed to have a major role in inhibiting calcification in vascular cells, based on the dramatic phenotype of aortic ossification in the MGP-deficient mouse, and based on its ability to bind and inhibit BMP-213,14 which is also in the artery wall, as well as its potential to directly bind and block growth of hydroxyapatite crystals. To further complicate issues, vitamin D, which may also have limited uptake in the apoE null mouse, also regulates vascular calcification.15
Thus, it is conceivable that vascular calcification in apoE(–/–) mice is attributable to abnormal growth and differentiation of resident mesenchymal stem cells, in response to 2 factors: atherogenic lipids and unopposed activity of BMP due to undercarboxylation of MGP. In human atherosclerosis, there may be less effect on vitamin K and hence BMP activity, yielding osteogenic, rather than chondrogenic, ectopia.
References
Rattazzi M, Bennett BJ, Bea F, Kirk EA, Ricks JL, Speer M, Schwartz SM, Giachelli CM, Rosenfeld ME Calcification of advanced atherosclerotic lesions in the innominate arteries of apoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler Thromb Vasc Biol. 2005; 25: 1420–1426.
Cheng SL, Shao JS, Charlton-Kachigian N, Loewy AP, Towler DA. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J Biol Chem. 2003; 278: 45969–45977.
Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Bostrom K, Demer LL. Multilineage potential of cells from the artery wall. Circulation. 2003; 108: 2505–2510.
Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation. 2004; 110: 2226–2232.
Hunt JL, Fairman R, Mitchell ME, Carpenter JP, Golden M, Khalapyan T, Wolfe M, Neschis D, Milner R, Scoll B, Cusack A, Mohler ER3rd. Bone formation in carotid plaques: a clinicopathological study. Stroke. 2002; 33: 1214–1219.
Qiao JH, Fishbein MC, Demer LL, Lusis AJ. Genetic determination of cartilaginous metaplasia in mouse aorta. Arterioscler Thromb Vasc Biol. 1995; 15: 2265–2272.
Ahrens M, Ankenbauer T, Schroder D, Hollnagel A, Mayer H, Gross G. Expression of human bone morphogenetic proteins-2 or -4 in murine mesenchymal progenitor C3H10T1/2 cells induces differentiation into distinct mesenchymal cell lineages. DNA Cell Biol. 1993; 12: 871–880.
Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005; 115: 1210–1220.
Klein RF, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos AS, Shea M, Waters RV, Belknap JK, Peltz G, Orwoll ES. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science. 2004; 303: 229–232.
Schilling AF, Schinke T, Munch C, Gebauer M, Niemeier A, Priemel M, Streichert T, Rueger JM, Amling M. Increased bone formation in mice lacking apolipoprotein E. J Bone Miner Res. 2005; 20: 274–282.
Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL. Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol. 1998; 18: 379–388.
Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998; 18: 1400–1407.
Bostrom K, Tsao D, Shen S, Wang Y, Demer LL. Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem. 2001; 276: 14044–14052.
Wallin R, Cain D, Hutson SM, Sane DC, Loeser R. Modulation of the binding of matrix Gla protein (MGP) to bone morphogenetic protein-2 (BMP-2). Thromb Haemost. 2000; 84: 1039–1044.
Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000; 20: 317–327.(Linda L. Demer; Yin Tintu)