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Possible role of oxidized lipids in osteoporosis: could hyperlipidemia be a risk factor?
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Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 373–378
Possible role of oxidized lipids in osteoporosis: could hyperlipidemia be a risk factor? Farhad Parhami* UCLA Division of Cardiology, Center for the Health Sciences 47-123, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA Received 3 December 2002; accepted 20 December 2002
Abstract Several years ago we hypothesized that products of lipid and lipoprotein oxidation may contribute to pathophysiology of osteoporosis (F. Parhami, Curr. Opin. Lipidol. 8 (1997) 312), and that their effects on artery wall and bone cells may explain the parallel development of osteoporosis and atherosclerosis in the same subjects (R. Boukhris, JAMA 219 (1972) 1307; M.A. Frye, Bone Miner. 19 (1992) 185). Since then, new evidence has accumulated in support of this hypothesis and its possibility is being further tested by investigators in both vascular and bone fields (A.D. Watson, J. Biol. Chem. 272 (1997) 13597). This review will summarize the evidence to date that support the role of oxidized lipids in osteoporosis, and will address some of the issues that need further examination in order to establish whether hyperlipidemia and susceptibility to lipid oxidation may serve as risk factors for osteoporosis. r 2003 Elsevier Science Ltd. All rights reserved.
1. Effects of oxidized lipids on osteoblastic and osteoclastic cells The original observation suggesting that oxidized lipids might play a role in bone cell function was the inhibition of osteoblastic differentiation upon treatment with certain oxidized lipids and lipoproteins [1–3]. Agents that caused this inhibition included minimally oxidized LDL (MM-LDL), isoprostane 8-isoprostaglandin E2 (isoPGE2), and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphoryl choline (Ox-PAPC), an oxidized phospholipid component of MM-LDL [4]. MM-LDL, Ox-PAPC and isoprostanes have all been identified as oxidized lipids that can promote inflammatory responses of artery wall cells that initiate the atherosclerotic lesion formation [5]. When applied to MC3T3-E1 preosteoblastic cells, these factors inhibited differentiation as demonstrated by the inhibition of alkaline phosphatase activity, extracellular matrix maturation, and mineralization [6]. Osteoporosis is in part a result of diminished bone formation by osteoblasts with aging. Thus, we hypothesized that if, similar to the artery wall, lipoproteins and lipids accumulate in bone *Tel.: +1-310-825-5729; fax: +1-310-206-9133. E-mail address: [email protected] (F. Parhami).
and undergo oxidation [7], they may affect the cellular constituents of bone including the osteoblastic cells and inhibit their proper bone-forming activity. This seems quite plausible since bone contains a significant number of blood vessels, with cellular constituents of bone located in close proximity to the interwoven vascular beds, and accumulation of lipids in the osteons of human osteoporotic bone has been demonstrated [8]. Subsequently, we demonstrated that similar to the effects seen with MC3T3-E1 cells, marrow stromal cells (MSCs) are also inhibited from differentiating into osteoblastic cells when treated with oxidized lipids [9]. Treatment with MM-LDL inhibited the osteoblastic differentiation of mouse MSC line M2-10B4, whereas adipogenic differentiation was enhanced [9]. This is particularly important since decreased number and osteogenic activity of MSCs parallels their increased differentiation into adipocytes in osteoporotic bones of humans [10,11]. Thus, actions of oxidized lipids on MSC may at least in part explain the progressive impairment of their osteoblastic differentiation potential with age and in osteoporosis. The anti-osteogenic effects of MMLDL on MSCs are mediated in part through activation of the MAPK pathway [9], and through cellular oxidant stress induced by the formation of reactive oxygen species [12]. Furthermore, the effects of the oxidized
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lipids are reversed by the inhibitor of MAPK kinase, PD98058, and by treatment with the antioxidant Trolox [9,12]. Recently, we demonstrated that oxidized lipids might exert their adverse effects on bone by targeting osteoclastic cells as well as osteoblastic cells. Osteoporotic bone loss is in part due to enhanced bone resorption as a result of increased osteoclastic activity [13]. Treatment of mouse marrow preosteoclasts with isoPGE2, oxidized LDL, or Ox-PAPC induced the RANKL-dependent osteoclastic differentiation of these cells as demonstrated by increased TRAP activity, formation of multinucleated cells, and mineral resorption. The stimulatory effects of the oxidized lipids on osteoclastic differentiation were induced via a cAMPmediated pathway [14].
The effects of oxidized lipids on bone cells may be caused through direct interactions with the cells via receptor-mediated responses and/or through generation of other inflammatory factors such as cytokines that may then produce the observed effects of the oxidized lipids on bone cells (Fig. 1). Oxidized lipids induce the expression of cytokines such as MCP-1, M-CSF and IL-6 both in vitro and in vivo [15,16]. We speculate that the generation of these inflammatory cytokines as well as others by bone cells, or the cells of the immune system, in response to oxidized lipids may in part mediate the anti-osteogenic and pro-resorptive effects of oxidized lipids in bone (Fig. 1). This would be consistent with the previously suggested role of immune cells and cytokines in osteoporotic bone loss [17–19].
Lipids and Lipoproteins
Reduced antioxidant defense systems
1
Increased levels and susceptibility to oxidation
Lipid oxidation and accumulation in bone
3 2 Inflammation and production of inflammatory cytokines
Inhibition of osteoblastic differentiation Decreased bone formation by osteoblastic cells
4
Increased adipogenesis of marrow stromal cells
Induction of osteoclastic differentiation Increased bone resorption by osteoclastic cells
Osteoporosis Fig. 1. Possible role of lipid oxidation in osteoporosis—aging is associated with reduced antioxidant defense systems, increased levels of circulating lipids and lipoproteins, and a greater susceptibility of those particles to oxidation. This may result in increased lipid and lipoprotein accumulation and oxidation in bone (1). The oxidized lipids may have direct adverse effects on cellular components of bone, inhibiting osteoblastic differentiation and bone formation, increasing adipogenesis of MSCs at the expense of their osteogenic differentiation, and inducing osteoclastic differentiation and bone resorption (2). Oxidized lipids may also affect bone cells indirectly through the induction of an inflammatory response and production of cytokines (3), which can subsequently affect the phenotype and activity of bone cells, acting either alone and/or in synergy with oxidized lipids (4). All these factors may contribute to the pathogenesis of osteoporosis.
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2. Effects of hyperlipidemia on bone MSCs In order to examine the possible effects of hyperlipidemia and subsequent formation of lipid oxidation products on MSC differentiation, we used C57BL/6 mice that are susceptible to hyperlipidemia, lipid oxidation, and atherosclerotic lesion formation when placed on an atherogenic high fat diet [20]. After 2 months on this diet, MSC obtained from long bones demonstrated significant decline in their ability to undergo osteoblastic differentiation [9]. In contrast, MSC obtained from mice fed a normal chow diet, which does not induce hyperlipidemia, demonstrated robust osteoblastic differentiation and formed a mineralized matrix [9]. Interestingly, the inhibitory effects of the atherogenic diet on the MSC were sustained during at least four cell passages in vitro, indicating that the effects are not merely due to changes in the bone marrow milieu but were more likely due to direct effects on the cells themselves. Changes in the lipid profile of the bone marrow after feeding diets rich in specific fats have been demonstrated [21]. In ongoing studies we are characterizing changes in oxidized lipid content in the bone marrow of mice fed an atherogenic diet in order to establish a stronger link between the accumulation of oxidized lipids and their adverse effects on MSC and bone. Generation of oxidized lipids in tissues in a hyperlipidemic state occurs in part through the activity of members of the lipoxygenase family of enzymes that generate a variety of bioactive and inflammatory lipids [22,23]. Interestingly, mice lacking the enzyme 5-lipoxygenase have increased cortical bone thickness [24], while 5-lipoxygenase products inhibit osteoblastic differentiation in vitro [25]. This suggests that 5-lipoxygenase activity may contribute to the formation of oxidized lipids in bones of hyperlipidemic mice and that 5-lipoxygenase products may mediate the adverse effects of hyperlipidemia on MSC. In preliminary studies we have found that products of 5-lipoxygenase appear to be increased in lipid extracts from bone marrow of mice on the atherogenic high fat diet compared to mice fed a normal chow diet, as determined by mass spectrometric analysis (A.D. Watson, F. Parhami 2002, unpublished observations). Recently, 5-lipoxygenase was also identified as a major gene contributing to atherosclerosis susceptibility in mice [26].
3. Effects of hyperlipidemia on bones of mice In order to examine the effects of hyperlipidemia and lipid oxidation on bone, two strains of mice were placed on a normal chow or atherogenic high fat diet. As noted previously, C57BL/6 mice on atherogenic diet develop atherosclerotic lesions as a result of hyperlipidemia, lipid
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oxidation, and inflammatory responses of artery wall cells to those oxidized lipids. In contrast, C3H/HeJ mice are resistant to the effects of atherogenic diet and oxidized lipids, and hence do not develop atherosclerosis [20]. After 7 months on the atherogenic diet, the C57BL/6 mice developed osteopenia of their vertebrae and femurs as evidenced by diminished bone mineral content and bone mineral density measured by peripheral quantitative computed tomographic (pQCT) scanning [27]. In contrast, the C3H/HeJ mice were resistant to the adverse effects of the atherogenic diet on bone, suggesting that similar mechanisms that protect their arteries may also protect their bones against the adverse effects of hyperlipidemia. Further characterization of the mechanisms underlying such differences in these two mouse strains may further elucidate the genetic components of susceptibility and resistance to lipid-induced osteoporotic bone loss. Interestingly, these two strains of mice have been the subject of studies of the genetic components of bone homeostasis [28,29], since the C3H/HeJ mice have higher peak bone mass than the C57BL/6 mice [30]. In fact, variation in genetic susceptibility to the development of atherosclerosis and low bone mineral density among inbred strains of mice demonstrates that C3H/HeJ mice are the least susceptible and C57BL/6 mice are the most susceptible to the development of both diseases [20,30]. It is intriguing to speculate that the underlying basis for these differences in bone mass might be the different susceptibility of these mice to oxidant stress-mediated events, including the formation of oxidized lipids and subsequent oxidative damage to tissues, as well as differences in relative ability to combat the effects of oxidant stress. For example, it has been demonstrated that after feeding these mice an atherogenic diet, HDL isolated from the resistant C3H/HeJ mice remains capable of inhibiting oxidative modification of LDL, whereas HDL isolated from the susceptible C57BL/6 mice loses its protective capacity [31]. Such changes in HDL protective capacity are correlated with changes in levels of the HDL-associated protective enzyme paraoxonase [31]. Consistently, on the atherogenic diet, C57BL/6 mice accumulate significantly greater amounts of oxidized lipids and demonstrate greater expression of oxidant stress-induced genes in their livers compared to C3H/HeJ mice [32]. Future studies will determine whether cause and effect relationships exist between bone quality and susceptibility to oxidant stress, antioxidant capacity and cellular responses to oxidant stress.
4. Other evidence and future considerations Epidemiological evidence links osteoporosis with cardiovascular disease, independent of age [2,3].
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Low bone mineral density is associated closely with atherosclerosis [33,34], cardiovascular calcification [35–37], and cardiovascular disease mortality [38–40]. Such correlations raise the possibility of a common underlying factor or mechanism. The important role of lipids and lipid oxidation in cardiovascular disease is well established [15,41,42], and we believe that oxidized lipids may at least in part serve as common mediators of cardiovascular disease and osteoporosis. Hypercholesterolemia is an important risk factor for atherosclerosis [43], and we speculate that it may also serve as a risk factor for osteoporosis. In support of this speculation, correlations between high serum cholesterol and osteoporosis have been noted. In a population study of 241 osteoporotic and 98 age-matched normal Czech women, Broulik et al. [44] found significantly higher serum cholesterol levels in the osteoporotic women. Similarly, Semmler [45] reported the correlation between hypercholesterolemia and osteoporosis in men. More recently, Yamaguchi et al. [46] reported an inverse relationship between bone mineral density and LDL–cholesterol levels, and a direct relationship between bone mineral density and HDL–cholesterol levels. Similar relationships between bone mineral density and lipoprotein levels in mice were reported earlier by Drake et al. [47]. However, using data from the Framingham Osteoporosis Study over 34 years, Samelson et al. [48] were unable to show a strong correlation between lipoprotein levels and bone mineral density, although there was some suggestion of an inverse association between total cholesterol levels and bone mineral density that was not consistent for women and men or for all bone sites evaluated. We believe that such variations in results may be due to the complex nature of the relationship between lipids and bone, and the effects of genetic variations on the response to hyperlipidemia. First, as is the case with atherosclerosis [49], cholesterol is perhaps not directly responsible for the adverse effects of hypercholesterolemia on bone; the culprits are more likely to be the bioactive products of lipid and lipoprotein oxidation that affect bone formation and resorption. Therefore, in examining relationships between lipids and bone in epidemiological studies, perhaps the formation and accumulation of oxidized lipids and lipoproteins, both in circulation and in bone, should be evaluated. Second, again similar to atherosclerosis, HDL levels and LDL/ HDL ratios as well as the protective capacity of HDL particles, and perhaps other antioxidant defense mechanisms, are also likely to determine any adverse effects that oxidized lipids might exert on bone [50–52]. Thus, although the number of years and the extent of hyperlipidemia may be important, parameters that regulate lipid oxidation and oxidant stress levels might also be critical. Indeed, in general, serum lipid and lipid peroxide levels increase with age in humans [53], and aging correlates with a decrease in antioxidant defense
systems, and an increase in the level of free radicals that promote the oxidation of biomolecules such as lipids, proteins, and DNA [54]. It is therefore plausible to hypothesize that increased oxidation of lipids and lipoproteins with aging leads to the progressive accumulation of these products within bone, as well as within the artery wall. Lipid oxidation products could in turn cause adverse effects on bone formation and resorption, contributing to the reduction in bone mineral density with age. Future studies will further test this hypothesis and will evaluate the possible use of existing and newly developing anti-lipid strategies in the fight against osteoporosis as well as cardiovascular disease.
Acknowledgements The author would like to thank Drs. Theodore J. Hahn, Sotirios Tetradis and Andrew D. Watson for reading this manuscript. The author’s research described in this manuscript were supported in part by National Institute of Aging Pepper Center Grant AG10415, NIH Grant HL30568, and the Laubisch Fund.
References [1] F. Parhami, L.L. Demer, Arterial calcification in face of osteoporosis in ageing: can we blame oxidized lipids?, Curr. Opin. Lipidol. 8 (1997) 312–314. [2] R. Boukhris, K.L. Becker, Calcification of the aorta and osteoporosis, JAMA 219 (1972) 1307–1311. [3] M.A. Frye, L.J. Melton, S.C. Bryant, L.A. Fitzpatrick, H.W. Wahner, R.S. Schwartz, B.L. Riggs, Osteoporosis and calcification of the aorta, Bone Miner. 19 (1992) 185–194. [4] A.D. Watson, N. Leitinger, M. Navab, K.F. Faull, S. Horkko, J.L. Witztum, W. Palinski, D. Schwenke, R.G. Salomon, W. Sha, G. Subbanagounder, A.M. Fogelman, J.A. Berliner, Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/ endothelial interactions and evidence for their presence in vivo, J. Biol. Chem. 272 (1997) 13597–13607. [5] J.L. Witztum, J.A. Berliner, Oxidized phospholipids and isoprostanes in atherosclerosis, Curr. Opin. Lipidol. 9 (1998) 441–448. [6] F. Parhami, A.D. Morrow, J. Balucan, N. Leitinger, A.D. Watson, Y. Tintut, J.A. Berliner, L.L. Demer, Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation, a possible explanation for the paradox of arterial calcification in osteoporotic patients, Arterioscler. Thromb. Vasc. Biol. 17 (1997) 680–687. [7] M. Navab, A.M. Fogelman, J.A. Berliner, M.C. Territo, L.L. Demer, J.S. Frank, A.D. Watson, P.A. Edwards, A.J. Lusis, Pathogenesis of atherosclerosis, Am. J. Cardiol. 76 (1995) 18C–23C. [8] E. Ramseier, Untersuchungen uber arteriosklerotische Veranderungen der Konchenarterien, Virchows Arch. Pathol. Anat. 336 (1962) 77–86. [9] F. Parhami, S.M. Jackson, Y. Tintut, V. Le, J.P. Balucan, M.C. Territo, L.L. Demer, Atherogenic diet and minimally
ARTICLE IN PRESS F. Parhami / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 373–378
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19] [20]
[21]
[22]
[23] [24]
[25]
[26]
[27]
[28]
oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells, J. Bone Miner. Res. 14 (1999) 2067–2078. P. Meunier, J. Aaron, C. Edouard, G. Vignon, Osteoporosis and the replacement of cell populations of the marrow by adipose tissue: a quantitative study of 84 iliac bone biopsies, Clin. Orthop. 80 (1971) 147–154. R. Burkhardt, G. Kettner, W. Bohm, M. Schmidmeir, R. Schlag, B. Frisch, B. Mallmann, W. Eisenmenger, T. Gilg, Changes in trabecular bone, hematopoeisis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study, Bone 8 (1987) 157–164. N. Mody, F. Parhami, T.A. Sarafian, L.L. Demer, Oxidative stress modulates osteoblastic differentiation of vascular and bone cells, Free Radical Biol. Med. 31 (2001) 509–519. S.C. Manolagas, Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis, Endocr. Rev. 21 (2000) 115–137. Y. Tintut, F. Parhami, A. Tsingotjidou, S. Tetradis, M. Territo, Demer 8-Isoprostaglandin E2 enhances receptor-activated NFkB ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway, J. Biol. Chem. 277 (2002) 14221–14226. J.A. Berliner, M. Navab, A.M. Fogelman, J.S. Frank, L.L. Demer, P.A. Edwards, A.D. Watson, A.J. Lusis, Atherosclerosis: basic mechanisms, Oxid. Inflammation Genet. Circ. 91 (1995) 2488–2496. B.J. Van Lenten, A.C. Wagner, M. Navab, A.M. Fogelman, Oxidized phospholipids induce changes in hepatic paraoxonase and apoJ but not monocyte chemoattractant protein-1 via interleukin-6, J. Biol. Chem. 276 (2001) 1923–1929. S.C. Manolagas, R.L. Jilka, Bone marrow cytokines and bone remodeling. Emerging insights into the pathophysiology of osteoporosis, N. Engl. J. Med. 332 (1995) 305–311. L.E. Theill, W.J. Boyle, J.M. Penninger, RANK-L and RANK: T cells bone loss and mammalian evolution, Annu. Rev. Immunol. 20 (2002) 795–823. W.B. Ershler, S.M. Harman, E.T. Keller, Immunologic aspects of osteoporosis, Dev. Comp. Immunol. 21 (1997) 487–499. B. Paigen, A. Morrow, C. Brandon, D. Mitchell, P. Holmes, Variation in susceptibility to atherosclerosis among inbred strains of mice, Atherosclerosis 57 (1985) 65–73. Y. Li, B.A. Watkins, Conjugated linoleic acids alter bone fatty acid composition and reduce ex vivo prostaglandin E2 biosynthesis in rats fed n-6 or n-3 fatty acids, Lipids 33 (1998) 417–425. D.J. Conrad, The arachidonate 12/15 lipoxygenases, A review of tissue expression biologic function, Clin. Rev. Allergy Immunol. 17 (1999) 71–89. A. Heller, T. Koch, J. Schmeck, K. van Ackern, Lipid mediators in inflammatory disorders, Drugs 55 (1998) 487–496. L.F. Bonewald, M. Flynn, M. Qiao, M.R. Dallas, G.R. Mundy, B.F. Boyce, Mice lacking 5-lipoxygenase have increased cortical bone thickness, Adv. Exp. Med. Biol. 433 (1997) 299–302. K. Traianedes, M.R. Dallas, I.R. Garrett, G.R. Mundy, L.F. Bonewald, 5-Lipoxygenase metabolites inhibit bone formation in vitro, Endocrinology 139 (1998) 3178–3184. M. Mehrabian, H. Allayee, J. Wong, W. Shih, X. Wang, Z. Shaposhnik, C.D. Funk, A.J. Lusis, Identification of 5lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice, Circ. Res. 91 (2002) 120–126. F. Parhami, F. Tintutx, W.G. Beamer, N. Gharavi, W. Goodman, L.L. Demer, Atherogenic high-fat diet reduces bone mineralization in mice, J. Bone Miner. Res. 16 (2001) 182–188. M.P. Akhter, U.T. Iwaniec, M.A. Covey, D.B. Cullen, B. Kimmel, R.R. Recker, Genetic variations in bone density
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43] [44]
[45] [46]
377
histomorphometry and strength in mice, Calcif. Tissue Int. 67 (2000) 337–344. W.G. Beamer, K.L. Shultz, L.R. Donahue, G.A. Churchill, S. Sen, J.R. Wergedal, D.J. Baylink, C.J. Rosen, Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice, J. Bone Miner. Res. 16 (2001) 1195–1206. W.G. Beamer, L.R. Donahue, C.J. Rosen, D.J. Baylink, Genetic variability in adult bone density among inbred strains of mice, Bone 18 (1996) 397–403. D.M. Shih, L. Gu, S. Hama, Y. Xia, M. Navab, A.M. Fogelman, A.J. Lusis, Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model, J. Clin. Invest. 97 (1996) 1630–1639. F. Liao, A. Andalibi, F.C. deBeer, A.M. Fogelman, A.J. Lusis, Genetic control of inflammatory gene induction and NF-kB-like transcription factor activation in response to an atherogenic diet in mice, J. Clin. Invest. 91 (1993) 2572–2579. M. Laroche, J.M. Pouilles, C. Ribot, P. Bendayan, J. Bernard, H. Boccalon, B. Mazieres, Comparison of the bone mineral content of the lower limbs in men with ischaemic atherosclerotic disease, Clin. Rheumatol. 13 (1994) 61–64. M. Laroche, L. Moulinier, E. Bon, A. Cantagrel, B. Mazieres, Renal tubular disorder and arteriopathy of the lower limbs: risk factors in osteoporosis in men?, Osteoporosis Int. 4 (1994) 309–313. K.G. Jie, M.L. Bots, C. Vermeer, J.C. Witteman, D.E. Grobbee, Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study, Calcif. Tissue Int. 59 (1996) 352–356. E.I. Barengoltz, M. Berman, S.C. Kukreja, T. Kouznetsova, C. Lin, E.V. Chomka, Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women, Calcif. Tissue Int. 62 (1998) 209–213. Y. Ouchi, M. Akishita, A.C. deSouza, T. Nakamura, H. Orimo, Age-related loss of bone mass and aortic/aortic valve calcification-reevaluation of the recommended dietary allowance of calcium in the elderly, Ann. N.Y. Acad. Sci. 676 (1993) 297–307. P. von der Recke, M.A. Hansen, C. Hassager, The association between low bone mass at the menopause and cardiovascular mortality, Am. J. Med. 106 (1999) 273–278. W.S. Browner, D.G. Seeley, T.M. Vogt, S.R. Cummings, Nontrauma mortality in elderly women with low bone mineral density, Lancet 338 (1991) 355–358. S. Naito, M. Ito, I. Sekine, T. Hirano, K. Iwasaki, M. Niwa, Femoral head necrosis and osteopenia in stroke-prone spontaneously hypertensive rats (SHRSPs), Bone 14 (1993) 745–753. M. Navab, J.A. Berliner, A.D. Watson, S.Y. Hama, M.C. Territo, A.J. Lusis, D.M. Shih, B.J. Van Lenten, J.S. Frank, L.L. Demer, P.E. Edwards, A.M. Fogelman, The Yin and Yang of oxidation in the development of the fatty streak, Arterioscl. Thromb. Vasc. Biol. 16 (1996) 831–842. J.L. Witztum, D. Steinberg, The oxidative modification hypothesis of atherosclerosis: does it hold for humans?, Trends Cardiovasc. Med. 11 (2001) 93–102. R. Ross, Atherosclerosis- an inflammatory disease, N. Engl. J. Med. 340 (1999) 115–126. P.D. Broulik, J. Kapitola, Interrelations between body weight, cigarette smoking and spine mineral density in osteoporotic Czech women, Endocr. Regul. 27 (1993) 57–60. J.C. Semmler, Risk Factors for Osteoporosis in Men. ICCRH, Florence (Abstract). T. Yamaguchi, T. Sugimoto, S. Yano, M. Yamauchi, H. Sowa, Q. Chen, K. Chihara, Plasma lipids in osteoporosis in postmenopausal women, Endocr. J. 49 (2002) 211–217.
ARTICLE IN PRESS 378
F. Parhami / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 373–378
[47] T.A. Drake, E. Schadt, K. Hannani, J.M. Kabo, K. Krass, V. Colinayo, L.E. Greaser, J. Goldin, A.J. Lusis, Genetic loci determining bone density in mice with diet-induced atherosclerosis, Physiol. Genomics 5 (2001) 205–215. [48] E.J. Samelson, L.A. Cupples, M.T. Hannan, P.W.F. Wilson, K.E. Broe, Y.Q. Zhang, D. Levy, S.A. Williams, V. Vaccarino, D.P. Kiel, Long-term effects of serum cholesterol over 34 years on bone mineral density (BMD) in women and men: the framingham osteoporosis study, J. Bone Miner. Res. 17 (1) (2002) S362 (Abstract). [49] J.L. Witztum, The oxidation hypothesis of atherosclerosis, Lancet 344 (1994) 793–795. [50] W.E. Boden, High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data
[51]
[52]
[53]
[54]
from Framingham to the veterans affairs high-density lipoprotein intervention trial, Am. J. Cardiol 86 (Suppl.) (2000) 19L–22L. J. Nofer, B. Kehrel, M. Fobker, B. Levkau, G. Assmann, A. von Eckardstein, HDL and arteriosclerosis: beyond reverse cholesterol transport, Atherosclerosis 161 (2002) 1–16. B.J. Van Lenten, M. Navab, D. Shih, A.M. Fogelman, A.J. Lusis, The role of high-density lipoproteins in oxidation and inflammation, Trends Cardiovasc. Med. 11 (2001) 155–161. J. Wallach, In: Interpretation of Diagnostic Tests: A Synopsis of Laboratory Medicine, 5th Edition, Little, Brown and Company, Boston/Toronto/London, Chapter 1, 1992, pp. 14–15. K.B. Beckman, B.N. Ames, The free radical theory of aging, Physiol. Rev. 78 (1998) 547–581.
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Possible role of oxidized lipids in osteoporosis: could hyperlipidemia be a risk factor? Farhad Parhami* UCLA Division of Cardiology, Center for the Health Sciences 47-123, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA Received 3 December 2002; accepted 20 December 2002
Abstract Several years ago we hypothesized that products of lipid and lipoprotein oxidation may contribute to pathophysiology of osteoporosis (F. Parhami, Curr. Opin. Lipidol. 8 (1997) 312), and that their effects on artery wall and bone cells may explain the parallel development of osteoporosis and atherosclerosis in the same subjects (R. Boukhris, JAMA 219 (1972) 1307; M.A. Frye, Bone Miner. 19 (1992) 185). Since then, new evidence has accumulated in support of this hypothesis and its possibility is being further tested by investigators in both vascular and bone fields (A.D. Watson, J. Biol. Chem. 272 (1997) 13597). This review will summarize the evidence to date that support the role of oxidized lipids in osteoporosis, and will address some of the issues that need further examination in order to establish whether hyperlipidemia and susceptibility to lipid oxidation may serve as risk factors for osteoporosis. r 2003 Elsevier Science Ltd. All rights reserved.
1. Effects of oxidized lipids on osteoblastic and osteoclastic cells The original observation suggesting that oxidized lipids might play a role in bone cell function was the inhibition of osteoblastic differentiation upon treatment with certain oxidized lipids and lipoproteins [1–3]. Agents that caused this inhibition included minimally oxidized LDL (MM-LDL), isoprostane 8-isoprostaglandin E2 (isoPGE2), and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphoryl choline (Ox-PAPC), an oxidized phospholipid component of MM-LDL [4]. MM-LDL, Ox-PAPC and isoprostanes have all been identified as oxidized lipids that can promote inflammatory responses of artery wall cells that initiate the atherosclerotic lesion formation [5]. When applied to MC3T3-E1 preosteoblastic cells, these factors inhibited differentiation as demonstrated by the inhibition of alkaline phosphatase activity, extracellular matrix maturation, and mineralization [6]. Osteoporosis is in part a result of diminished bone formation by osteoblasts with aging. Thus, we hypothesized that if, similar to the artery wall, lipoproteins and lipids accumulate in bone *Tel.: +1-310-825-5729; fax: +1-310-206-9133. E-mail address: [email protected] (F. Parhami).
and undergo oxidation [7], they may affect the cellular constituents of bone including the osteoblastic cells and inhibit their proper bone-forming activity. This seems quite plausible since bone contains a significant number of blood vessels, with cellular constituents of bone located in close proximity to the interwoven vascular beds, and accumulation of lipids in the osteons of human osteoporotic bone has been demonstrated [8]. Subsequently, we demonstrated that similar to the effects seen with MC3T3-E1 cells, marrow stromal cells (MSCs) are also inhibited from differentiating into osteoblastic cells when treated with oxidized lipids [9]. Treatment with MM-LDL inhibited the osteoblastic differentiation of mouse MSC line M2-10B4, whereas adipogenic differentiation was enhanced [9]. This is particularly important since decreased number and osteogenic activity of MSCs parallels their increased differentiation into adipocytes in osteoporotic bones of humans [10,11]. Thus, actions of oxidized lipids on MSC may at least in part explain the progressive impairment of their osteoblastic differentiation potential with age and in osteoporosis. The anti-osteogenic effects of MMLDL on MSCs are mediated in part through activation of the MAPK pathway [9], and through cellular oxidant stress induced by the formation of reactive oxygen species [12]. Furthermore, the effects of the oxidized
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lipids are reversed by the inhibitor of MAPK kinase, PD98058, and by treatment with the antioxidant Trolox [9,12]. Recently, we demonstrated that oxidized lipids might exert their adverse effects on bone by targeting osteoclastic cells as well as osteoblastic cells. Osteoporotic bone loss is in part due to enhanced bone resorption as a result of increased osteoclastic activity [13]. Treatment of mouse marrow preosteoclasts with isoPGE2, oxidized LDL, or Ox-PAPC induced the RANKL-dependent osteoclastic differentiation of these cells as demonstrated by increased TRAP activity, formation of multinucleated cells, and mineral resorption. The stimulatory effects of the oxidized lipids on osteoclastic differentiation were induced via a cAMPmediated pathway [14].
The effects of oxidized lipids on bone cells may be caused through direct interactions with the cells via receptor-mediated responses and/or through generation of other inflammatory factors such as cytokines that may then produce the observed effects of the oxidized lipids on bone cells (Fig. 1). Oxidized lipids induce the expression of cytokines such as MCP-1, M-CSF and IL-6 both in vitro and in vivo [15,16]. We speculate that the generation of these inflammatory cytokines as well as others by bone cells, or the cells of the immune system, in response to oxidized lipids may in part mediate the anti-osteogenic and pro-resorptive effects of oxidized lipids in bone (Fig. 1). This would be consistent with the previously suggested role of immune cells and cytokines in osteoporotic bone loss [17–19].
Lipids and Lipoproteins
Reduced antioxidant defense systems
1
Increased levels and susceptibility to oxidation
Lipid oxidation and accumulation in bone
3 2 Inflammation and production of inflammatory cytokines
Inhibition of osteoblastic differentiation Decreased bone formation by osteoblastic cells
4
Increased adipogenesis of marrow stromal cells
Induction of osteoclastic differentiation Increased bone resorption by osteoclastic cells
Osteoporosis Fig. 1. Possible role of lipid oxidation in osteoporosis—aging is associated with reduced antioxidant defense systems, increased levels of circulating lipids and lipoproteins, and a greater susceptibility of those particles to oxidation. This may result in increased lipid and lipoprotein accumulation and oxidation in bone (1). The oxidized lipids may have direct adverse effects on cellular components of bone, inhibiting osteoblastic differentiation and bone formation, increasing adipogenesis of MSCs at the expense of their osteogenic differentiation, and inducing osteoclastic differentiation and bone resorption (2). Oxidized lipids may also affect bone cells indirectly through the induction of an inflammatory response and production of cytokines (3), which can subsequently affect the phenotype and activity of bone cells, acting either alone and/or in synergy with oxidized lipids (4). All these factors may contribute to the pathogenesis of osteoporosis.
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2. Effects of hyperlipidemia on bone MSCs In order to examine the possible effects of hyperlipidemia and subsequent formation of lipid oxidation products on MSC differentiation, we used C57BL/6 mice that are susceptible to hyperlipidemia, lipid oxidation, and atherosclerotic lesion formation when placed on an atherogenic high fat diet [20]. After 2 months on this diet, MSC obtained from long bones demonstrated significant decline in their ability to undergo osteoblastic differentiation [9]. In contrast, MSC obtained from mice fed a normal chow diet, which does not induce hyperlipidemia, demonstrated robust osteoblastic differentiation and formed a mineralized matrix [9]. Interestingly, the inhibitory effects of the atherogenic diet on the MSC were sustained during at least four cell passages in vitro, indicating that the effects are not merely due to changes in the bone marrow milieu but were more likely due to direct effects on the cells themselves. Changes in the lipid profile of the bone marrow after feeding diets rich in specific fats have been demonstrated [21]. In ongoing studies we are characterizing changes in oxidized lipid content in the bone marrow of mice fed an atherogenic diet in order to establish a stronger link between the accumulation of oxidized lipids and their adverse effects on MSC and bone. Generation of oxidized lipids in tissues in a hyperlipidemic state occurs in part through the activity of members of the lipoxygenase family of enzymes that generate a variety of bioactive and inflammatory lipids [22,23]. Interestingly, mice lacking the enzyme 5-lipoxygenase have increased cortical bone thickness [24], while 5-lipoxygenase products inhibit osteoblastic differentiation in vitro [25]. This suggests that 5-lipoxygenase activity may contribute to the formation of oxidized lipids in bones of hyperlipidemic mice and that 5-lipoxygenase products may mediate the adverse effects of hyperlipidemia on MSC. In preliminary studies we have found that products of 5-lipoxygenase appear to be increased in lipid extracts from bone marrow of mice on the atherogenic high fat diet compared to mice fed a normal chow diet, as determined by mass spectrometric analysis (A.D. Watson, F. Parhami 2002, unpublished observations). Recently, 5-lipoxygenase was also identified as a major gene contributing to atherosclerosis susceptibility in mice [26].
3. Effects of hyperlipidemia on bones of mice In order to examine the effects of hyperlipidemia and lipid oxidation on bone, two strains of mice were placed on a normal chow or atherogenic high fat diet. As noted previously, C57BL/6 mice on atherogenic diet develop atherosclerotic lesions as a result of hyperlipidemia, lipid
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oxidation, and inflammatory responses of artery wall cells to those oxidized lipids. In contrast, C3H/HeJ mice are resistant to the effects of atherogenic diet and oxidized lipids, and hence do not develop atherosclerosis [20]. After 7 months on the atherogenic diet, the C57BL/6 mice developed osteopenia of their vertebrae and femurs as evidenced by diminished bone mineral content and bone mineral density measured by peripheral quantitative computed tomographic (pQCT) scanning [27]. In contrast, the C3H/HeJ mice were resistant to the adverse effects of the atherogenic diet on bone, suggesting that similar mechanisms that protect their arteries may also protect their bones against the adverse effects of hyperlipidemia. Further characterization of the mechanisms underlying such differences in these two mouse strains may further elucidate the genetic components of susceptibility and resistance to lipid-induced osteoporotic bone loss. Interestingly, these two strains of mice have been the subject of studies of the genetic components of bone homeostasis [28,29], since the C3H/HeJ mice have higher peak bone mass than the C57BL/6 mice [30]. In fact, variation in genetic susceptibility to the development of atherosclerosis and low bone mineral density among inbred strains of mice demonstrates that C3H/HeJ mice are the least susceptible and C57BL/6 mice are the most susceptible to the development of both diseases [20,30]. It is intriguing to speculate that the underlying basis for these differences in bone mass might be the different susceptibility of these mice to oxidant stress-mediated events, including the formation of oxidized lipids and subsequent oxidative damage to tissues, as well as differences in relative ability to combat the effects of oxidant stress. For example, it has been demonstrated that after feeding these mice an atherogenic diet, HDL isolated from the resistant C3H/HeJ mice remains capable of inhibiting oxidative modification of LDL, whereas HDL isolated from the susceptible C57BL/6 mice loses its protective capacity [31]. Such changes in HDL protective capacity are correlated with changes in levels of the HDL-associated protective enzyme paraoxonase [31]. Consistently, on the atherogenic diet, C57BL/6 mice accumulate significantly greater amounts of oxidized lipids and demonstrate greater expression of oxidant stress-induced genes in their livers compared to C3H/HeJ mice [32]. Future studies will determine whether cause and effect relationships exist between bone quality and susceptibility to oxidant stress, antioxidant capacity and cellular responses to oxidant stress.
4. Other evidence and future considerations Epidemiological evidence links osteoporosis with cardiovascular disease, independent of age [2,3].
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Low bone mineral density is associated closely with atherosclerosis [33,34], cardiovascular calcification [35–37], and cardiovascular disease mortality [38–40]. Such correlations raise the possibility of a common underlying factor or mechanism. The important role of lipids and lipid oxidation in cardiovascular disease is well established [15,41,42], and we believe that oxidized lipids may at least in part serve as common mediators of cardiovascular disease and osteoporosis. Hypercholesterolemia is an important risk factor for atherosclerosis [43], and we speculate that it may also serve as a risk factor for osteoporosis. In support of this speculation, correlations between high serum cholesterol and osteoporosis have been noted. In a population study of 241 osteoporotic and 98 age-matched normal Czech women, Broulik et al. [44] found significantly higher serum cholesterol levels in the osteoporotic women. Similarly, Semmler [45] reported the correlation between hypercholesterolemia and osteoporosis in men. More recently, Yamaguchi et al. [46] reported an inverse relationship between bone mineral density and LDL–cholesterol levels, and a direct relationship between bone mineral density and HDL–cholesterol levels. Similar relationships between bone mineral density and lipoprotein levels in mice were reported earlier by Drake et al. [47]. However, using data from the Framingham Osteoporosis Study over 34 years, Samelson et al. [48] were unable to show a strong correlation between lipoprotein levels and bone mineral density, although there was some suggestion of an inverse association between total cholesterol levels and bone mineral density that was not consistent for women and men or for all bone sites evaluated. We believe that such variations in results may be due to the complex nature of the relationship between lipids and bone, and the effects of genetic variations on the response to hyperlipidemia. First, as is the case with atherosclerosis [49], cholesterol is perhaps not directly responsible for the adverse effects of hypercholesterolemia on bone; the culprits are more likely to be the bioactive products of lipid and lipoprotein oxidation that affect bone formation and resorption. Therefore, in examining relationships between lipids and bone in epidemiological studies, perhaps the formation and accumulation of oxidized lipids and lipoproteins, both in circulation and in bone, should be evaluated. Second, again similar to atherosclerosis, HDL levels and LDL/ HDL ratios as well as the protective capacity of HDL particles, and perhaps other antioxidant defense mechanisms, are also likely to determine any adverse effects that oxidized lipids might exert on bone [50–52]. Thus, although the number of years and the extent of hyperlipidemia may be important, parameters that regulate lipid oxidation and oxidant stress levels might also be critical. Indeed, in general, serum lipid and lipid peroxide levels increase with age in humans [53], and aging correlates with a decrease in antioxidant defense
systems, and an increase in the level of free radicals that promote the oxidation of biomolecules such as lipids, proteins, and DNA [54]. It is therefore plausible to hypothesize that increased oxidation of lipids and lipoproteins with aging leads to the progressive accumulation of these products within bone, as well as within the artery wall. Lipid oxidation products could in turn cause adverse effects on bone formation and resorption, contributing to the reduction in bone mineral density with age. Future studies will further test this hypothesis and will evaluate the possible use of existing and newly developing anti-lipid strategies in the fight against osteoporosis as well as cardiovascular disease.
Acknowledgements The author would like to thank Drs. Theodore J. Hahn, Sotirios Tetradis and Andrew D. Watson for reading this manuscript. The author’s research described in this manuscript were supported in part by National Institute of Aging Pepper Center Grant AG10415, NIH Grant HL30568, and the Laubisch Fund.
References [1] F. Parhami, L.L. Demer, Arterial calcification in face of osteoporosis in ageing: can we blame oxidized lipids?, Curr. Opin. Lipidol. 8 (1997) 312–314. [2] R. Boukhris, K.L. Becker, Calcification of the aorta and osteoporosis, JAMA 219 (1972) 1307–1311. [3] M.A. Frye, L.J. Melton, S.C. Bryant, L.A. Fitzpatrick, H.W. Wahner, R.S. Schwartz, B.L. Riggs, Osteoporosis and calcification of the aorta, Bone Miner. 19 (1992) 185–194. [4] A.D. Watson, N. Leitinger, M. Navab, K.F. Faull, S. Horkko, J.L. Witztum, W. Palinski, D. Schwenke, R.G. Salomon, W. Sha, G. Subbanagounder, A.M. Fogelman, J.A. Berliner, Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/ endothelial interactions and evidence for their presence in vivo, J. Biol. Chem. 272 (1997) 13597–13607. [5] J.L. Witztum, J.A. Berliner, Oxidized phospholipids and isoprostanes in atherosclerosis, Curr. Opin. Lipidol. 9 (1998) 441–448. [6] F. Parhami, A.D. Morrow, J. Balucan, N. Leitinger, A.D. Watson, Y. Tintut, J.A. Berliner, L.L. Demer, Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation, a possible explanation for the paradox of arterial calcification in osteoporotic patients, Arterioscler. Thromb. Vasc. Biol. 17 (1997) 680–687. [7] M. Navab, A.M. Fogelman, J.A. Berliner, M.C. Territo, L.L. Demer, J.S. Frank, A.D. Watson, P.A. Edwards, A.J. Lusis, Pathogenesis of atherosclerosis, Am. J. Cardiol. 76 (1995) 18C–23C. [8] E. Ramseier, Untersuchungen uber arteriosklerotische Veranderungen der Konchenarterien, Virchows Arch. Pathol. Anat. 336 (1962) 77–86. [9] F. Parhami, S.M. Jackson, Y. Tintut, V. Le, J.P. Balucan, M.C. Territo, L.L. Demer, Atherogenic diet and minimally
ARTICLE IN PRESS F. Parhami / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 373–378
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19] [20]
[21]
[22]
[23] [24]
[25]
[26]
[27]
[28]
oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells, J. Bone Miner. Res. 14 (1999) 2067–2078. P. Meunier, J. Aaron, C. Edouard, G. Vignon, Osteoporosis and the replacement of cell populations of the marrow by adipose tissue: a quantitative study of 84 iliac bone biopsies, Clin. Orthop. 80 (1971) 147–154. R. Burkhardt, G. Kettner, W. Bohm, M. Schmidmeir, R. Schlag, B. Frisch, B. Mallmann, W. Eisenmenger, T. Gilg, Changes in trabecular bone, hematopoeisis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study, Bone 8 (1987) 157–164. N. Mody, F. Parhami, T.A. Sarafian, L.L. Demer, Oxidative stress modulates osteoblastic differentiation of vascular and bone cells, Free Radical Biol. Med. 31 (2001) 509–519. S.C. Manolagas, Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis, Endocr. Rev. 21 (2000) 115–137. Y. Tintut, F. Parhami, A. Tsingotjidou, S. Tetradis, M. Territo, Demer 8-Isoprostaglandin E2 enhances receptor-activated NFkB ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway, J. Biol. Chem. 277 (2002) 14221–14226. J.A. Berliner, M. Navab, A.M. Fogelman, J.S. Frank, L.L. Demer, P.A. Edwards, A.D. Watson, A.J. Lusis, Atherosclerosis: basic mechanisms, Oxid. Inflammation Genet. Circ. 91 (1995) 2488–2496. B.J. Van Lenten, A.C. Wagner, M. Navab, A.M. Fogelman, Oxidized phospholipids induce changes in hepatic paraoxonase and apoJ but not monocyte chemoattractant protein-1 via interleukin-6, J. Biol. Chem. 276 (2001) 1923–1929. S.C. Manolagas, R.L. Jilka, Bone marrow cytokines and bone remodeling. Emerging insights into the pathophysiology of osteoporosis, N. Engl. J. Med. 332 (1995) 305–311. L.E. Theill, W.J. Boyle, J.M. Penninger, RANK-L and RANK: T cells bone loss and mammalian evolution, Annu. Rev. Immunol. 20 (2002) 795–823. W.B. Ershler, S.M. Harman, E.T. Keller, Immunologic aspects of osteoporosis, Dev. Comp. Immunol. 21 (1997) 487–499. B. Paigen, A. Morrow, C. Brandon, D. Mitchell, P. Holmes, Variation in susceptibility to atherosclerosis among inbred strains of mice, Atherosclerosis 57 (1985) 65–73. Y. Li, B.A. Watkins, Conjugated linoleic acids alter bone fatty acid composition and reduce ex vivo prostaglandin E2 biosynthesis in rats fed n-6 or n-3 fatty acids, Lipids 33 (1998) 417–425. D.J. Conrad, The arachidonate 12/15 lipoxygenases, A review of tissue expression biologic function, Clin. Rev. Allergy Immunol. 17 (1999) 71–89. A. Heller, T. Koch, J. Schmeck, K. van Ackern, Lipid mediators in inflammatory disorders, Drugs 55 (1998) 487–496. L.F. Bonewald, M. Flynn, M. Qiao, M.R. Dallas, G.R. Mundy, B.F. Boyce, Mice lacking 5-lipoxygenase have increased cortical bone thickness, Adv. Exp. Med. Biol. 433 (1997) 299–302. K. Traianedes, M.R. Dallas, I.R. Garrett, G.R. Mundy, L.F. Bonewald, 5-Lipoxygenase metabolites inhibit bone formation in vitro, Endocrinology 139 (1998) 3178–3184. M. Mehrabian, H. Allayee, J. Wong, W. Shih, X. Wang, Z. Shaposhnik, C.D. Funk, A.J. Lusis, Identification of 5lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice, Circ. Res. 91 (2002) 120–126. F. Parhami, F. Tintutx, W.G. Beamer, N. Gharavi, W. Goodman, L.L. Demer, Atherogenic high-fat diet reduces bone mineralization in mice, J. Bone Miner. Res. 16 (2001) 182–188. M.P. Akhter, U.T. Iwaniec, M.A. Covey, D.B. Cullen, B. Kimmel, R.R. Recker, Genetic variations in bone density
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43] [44]
[45] [46]
377
histomorphometry and strength in mice, Calcif. Tissue Int. 67 (2000) 337–344. W.G. Beamer, K.L. Shultz, L.R. Donahue, G.A. Churchill, S. Sen, J.R. Wergedal, D.J. Baylink, C.J. Rosen, Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice, J. Bone Miner. Res. 16 (2001) 1195–1206. W.G. Beamer, L.R. Donahue, C.J. Rosen, D.J. Baylink, Genetic variability in adult bone density among inbred strains of mice, Bone 18 (1996) 397–403. D.M. Shih, L. Gu, S. Hama, Y. Xia, M. Navab, A.M. Fogelman, A.J. Lusis, Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model, J. Clin. Invest. 97 (1996) 1630–1639. F. Liao, A. Andalibi, F.C. deBeer, A.M. Fogelman, A.J. Lusis, Genetic control of inflammatory gene induction and NF-kB-like transcription factor activation in response to an atherogenic diet in mice, J. Clin. Invest. 91 (1993) 2572–2579. M. Laroche, J.M. Pouilles, C. Ribot, P. Bendayan, J. Bernard, H. Boccalon, B. Mazieres, Comparison of the bone mineral content of the lower limbs in men with ischaemic atherosclerotic disease, Clin. Rheumatol. 13 (1994) 61–64. M. Laroche, L. Moulinier, E. Bon, A. Cantagrel, B. Mazieres, Renal tubular disorder and arteriopathy of the lower limbs: risk factors in osteoporosis in men?, Osteoporosis Int. 4 (1994) 309–313. K.G. Jie, M.L. Bots, C. Vermeer, J.C. Witteman, D.E. Grobbee, Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study, Calcif. Tissue Int. 59 (1996) 352–356. E.I. Barengoltz, M. Berman, S.C. Kukreja, T. Kouznetsova, C. Lin, E.V. Chomka, Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women, Calcif. Tissue Int. 62 (1998) 209–213. Y. Ouchi, M. Akishita, A.C. deSouza, T. Nakamura, H. Orimo, Age-related loss of bone mass and aortic/aortic valve calcification-reevaluation of the recommended dietary allowance of calcium in the elderly, Ann. N.Y. Acad. Sci. 676 (1993) 297–307. P. von der Recke, M.A. Hansen, C. Hassager, The association between low bone mass at the menopause and cardiovascular mortality, Am. J. Med. 106 (1999) 273–278. W.S. Browner, D.G. Seeley, T.M. Vogt, S.R. Cummings, Nontrauma mortality in elderly women with low bone mineral density, Lancet 338 (1991) 355–358. S. Naito, M. Ito, I. Sekine, T. Hirano, K. Iwasaki, M. Niwa, Femoral head necrosis and osteopenia in stroke-prone spontaneously hypertensive rats (SHRSPs), Bone 14 (1993) 745–753. M. Navab, J.A. Berliner, A.D. Watson, S.Y. Hama, M.C. Territo, A.J. Lusis, D.M. Shih, B.J. Van Lenten, J.S. Frank, L.L. Demer, P.E. Edwards, A.M. Fogelman, The Yin and Yang of oxidation in the development of the fatty streak, Arterioscl. Thromb. Vasc. Biol. 16 (1996) 831–842. J.L. Witztum, D. Steinberg, The oxidative modification hypothesis of atherosclerosis: does it hold for humans?, Trends Cardiovasc. Med. 11 (2001) 93–102. R. Ross, Atherosclerosis- an inflammatory disease, N. Engl. J. Med. 340 (1999) 115–126. P.D. Broulik, J. Kapitola, Interrelations between body weight, cigarette smoking and spine mineral density in osteoporotic Czech women, Endocr. Regul. 27 (1993) 57–60. J.C. Semmler, Risk Factors for Osteoporosis in Men. ICCRH, Florence (Abstract). T. Yamaguchi, T. Sugimoto, S. Yano, M. Yamauchi, H. Sowa, Q. Chen, K. Chihara, Plasma lipids in osteoporosis in postmenopausal women, Endocr. J. 49 (2002) 211–217.
ARTICLE IN PRESS 378
F. Parhami / Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 373–378
[47] T.A. Drake, E. Schadt, K. Hannani, J.M. Kabo, K. Krass, V. Colinayo, L.E. Greaser, J. Goldin, A.J. Lusis, Genetic loci determining bone density in mice with diet-induced atherosclerosis, Physiol. Genomics 5 (2001) 205–215. [48] E.J. Samelson, L.A. Cupples, M.T. Hannan, P.W.F. Wilson, K.E. Broe, Y.Q. Zhang, D. Levy, S.A. Williams, V. Vaccarino, D.P. Kiel, Long-term effects of serum cholesterol over 34 years on bone mineral density (BMD) in women and men: the framingham osteoporosis study, J. Bone Miner. Res. 17 (1) (2002) S362 (Abstract). [49] J.L. Witztum, The oxidation hypothesis of atherosclerosis, Lancet 344 (1994) 793–795. [50] W.E. Boden, High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data
[51]
[52]
[53]
[54]
from Framingham to the veterans affairs high-density lipoprotein intervention trial, Am. J. Cardiol 86 (Suppl.) (2000) 19L–22L. J. Nofer, B. Kehrel, M. Fobker, B. Levkau, G. Assmann, A. von Eckardstein, HDL and arteriosclerosis: beyond reverse cholesterol transport, Atherosclerosis 161 (2002) 1–16. B.J. Van Lenten, M. Navab, D. Shih, A.M. Fogelman, A.J. Lusis, The role of high-density lipoproteins in oxidation and inflammation, Trends Cardiovasc. Med. 11 (2001) 155–161. J. Wallach, In: Interpretation of Diagnostic Tests: A Synopsis of Laboratory Medicine, 5th Edition, Little, Brown and Company, Boston/Toronto/London, Chapter 1, 1992, pp. 14–15. K.B. Beckman, B.N. Ames, The free radical theory of aging, Physiol. Rev. 78 (1998) 547–581.