Escolar Documentos
Profissional Documentos
Cultura Documentos
Saunders Company
315
Osteoarthritis
VITAMINS AND ARTHRITIS
The Roles of Vitamins A, C, D, and E
Interactions between all of the major joint tissues, including articular cartilage,
synovium, and subchondral bone, have been implicated in the pathogenesis of
osteoarthritis (OA).
The pathogenetic mechanisms underlying the
development of OA are not fully understood; likewise, those factors that sustain or
impede the progression of OA are poorly identified. Nevertheless, patients
frequently have sought explanations for the development and progression of OA in
dietary practices and nutritional deficiencies from either their health care provider
or popular media. Enticing promises have been offered over the decades for
inexpensive nutritional supplements that will end the individual's misery. Currently,
there is much attention directed toward the use of antioxidant vitamins, and of
vitamin D, as a means of preventing or ameliorating the pain and disability of OA.
This attention is driven, in part, by our expanding appreciation of nutrition factors,
[24] [53] [69]
particularly the vitamins, that contribute to oxidate processes and bone turnover
that may be intrinsic to the development and progression of OA.
Vitamins A, C, and, E are the major antioxidants in the diet or in dietary
supplement products that have been identified as having a potential for antioxidant
activity in the processes associated with OA. Vitamin D also may play an important
role in OA by way of bone.
316
[42] [54]
[45] [64]
[20] [45]
The roles of nutrients in the OA processes are complex because of the interactive system
in which they operate. For example, reactive oxygen species are produced endogenously
in normal metabolism, and exogenously as a consequence of toxins, infection, injury,
radiation, and excessive exercise. Although mechanisms exist within the body to
protect tissues from excessive oxidative action, production of ROS can overwhelm those
modulating factors. In those instances in which anabolic and catabolic activities become
unbalanced, tissue damage can result, especially in extracellular spaces where antioxidant
enzymes are not as prevalent.
[38]
When free radicals attack polyunsaturated fatty acids (PUFA) in membrane lipids, they
create lipid peroxides, which spontaneously decompose to form lipid radicals. PUFAs,
with their double bonds, are readily attacked by free radicals and oxidized to lipid
peroxides, which have the capacity to damage cells. The free radicals produced by lipid
peroxidation, peroxyl radicals, are capable of removing hydrogen from adjacent fatty acid
side chains, thereby propagating a chain reaction known as lipid peroxidation. A single
initiating event can lead to hundreds of such events (Fig. 1) .
[38]
The production of free radicals also can be the consequence of tissue damage associated
with arthritis. Oxidative stress is believed to contribute to the progression of arthritis
rather than the initiation of disease.
[37]
317
Figure 1. Lipid peroxidation. ROS = reactive oxygen species; PUFA = polyunsaturated fatty acids; OA =
osteoarthritis.
With injury and tissue damage, mast cells release inflammatory mediators that increase
vascular permeability and permit complement and cells to enter tissues from the
circulation. The mast cells also promote the activity of polymorphonuclear neutrophils
(PMNs). The activities of PMNs and mast cells create an acute inflammatory response
that leads to removal of damaged tissues and cells, tissue repair, and healing. Once
macrophages are engaged, there is a potential for further cell-mediated response
involving natural killer (NK) cells. These activities can lead to phagocytosis and chronic
inflammation.
Chondrocytes are normally surrounded by an extracellular matrix (ECM) and a repair
process is initiated when this matrix is removed. Degradation and loss of the articular
cartilage matrix is a central feature of OA. This loss of matrix is accompanied by an
increased synthesis of matrix molecules, a process thought to be involved in matrix
repair.
[38] [39] [49]
318
Cellular Differentiation
Vitamin A and vitamin D are now recognized as fundamental elements of cellular
maturation and cellular differentiation. Retinoic acid, an oxidized form of vitamin A,
regulates embryonic development and the differentiation of epithelial and mesenchymal
tissues throughout life. Vitamin D has a role in the differentiation of keratocytes
and monocytes into macrophages.
Vitamin D also appears to act upon Tlymphocytes, which produce a variety of lymphokines, including the potent bone
resorbing agent, osteoclast activating factor.
[67]
[23] [52]
[40]
It is noteworthy that there are multiple mechanisms through which nutrients can have an
effect on either the initiation or progression of OA. For the most part, however, studies in
this area have been limited to laboratory investigations in tissue culture systems and
await extension into clinical or epidemiologic populations. On the other hand, the basic
research data on these nutrients (and their potential for ameliorating disease) have been
evoked inappropriately as scientific disguises for marketing strategies. Nonetheless, their
potential importance to OA reinforces the need for well-developed investigations in both
affected clinical and at-risk populations.
319
The Recommended Daily Allowance (RDA) for vitamin A is given in retinol equivalents
(RE) of active retinol (1 RE 1 mug 3.33 IU). One RE of beta-carotene is 6 mug
10 IU. The adult male RDA for vitamin A is 1000 RE per day and 800 RE per day for
an adult female. Vitamin A is found as retinol in foods such as liver, egg yolk, milk, and
other dairy products, whereas beta-carotene is found in dark green and yellow vegetables
and fruits.
[11] [61]
Although vitamin A toxicity is not common, it can occur when excess amounts of
supplements or major dietary sources, such as liver, are consumed. beta-carotene, on the
other hand, is rarely considered toxic, but can accumulate, giving the skin an orangeyellow hue.
Role of Vitamin A and Carotenoids in Oxidative Stress
Recent studies have demonstrated the antioxidant functions of beta-carotene and
carotenoids, in general, and their effective ability to scavenge singlet oxygen.
Carotenoids are known to scavenge and deactivate free radicals both in vitro and in vivo.
Evidence from in vitro experiments
suggests that beta-carotene may exert other
antioxidant effects, including inhibition of lipid peroxidation. Whereas some antioxidants
prevent the initiation of lipid peroxidation, beta-carotene controls the chain reactions by
trapping free radicals, complementing the action of other antioxidant molecules.
[11]
320
[28]
Another carotenoid, lycopene, is less abundant in the diet than beta-carotene. Like betacarotene, however, it is a singlet oxygen quencher and therefore can act also as an
antioxidant. Little data on this carotenoid are presently available.
[27]
[78]
[76]
beta-carotene has been shown to stimulate rat lymphocyte mitogenesis in vivo. In vitro
studies of the actions of beta-carotene have demonstrated that it increases the numbers of
human NK cells and T-helper cells.
Animal studies have shown that carotenoids
enhance immune function independent of any provitamin A effect.
Carotenoids have
been shown to enhance macrophage function, thereby modulating the production of
reactive oxygen species and controlling actions of other immune cells.
[12]
[2] [77]
[9] [10]
[9]
Using animal models, Pasatiempo et al have shown that normal antibody function is
impaired in early stages of vitamin A deficiency. Bowman et al have shown decreases
in NK cell activity and in interferon (IFN) production in the presence of vitamin A
deficiency.
[62]
[16]
Much of the research on the effects of carotenoids on human immune responses has been
limited to beta-carotene. Watson et al reported that supplementation of healthy older
adults with 30 to 60 mg a day of beta-carotene for 2 months significantly enhanced the
percentage of leukocytes in peripheral blood with cell receptors indicative of NK cells
and of lymphocytes with interleukin-2 (IL-2) receptors. In that study, plasma levels of
beta-carotene, but not of retinol, were significantly elevated, suggesting that modulation
of the immune system may have been induced by carotenoid activity rather than by the
action of vitamin A.
[77]
[77]
321
The RDA of 60 mg for adults is based on the amount needed to prevent the onset of
scorbutic symptoms for 4 weeks and provide a margin of safety. An increased intake of
vitamin C is required to maintain normal plasma or cellular levels in the presence of
acute emotional or environmental stress, such as trauma, fever, infection, or elevated
environmental temperatures. Sources of dietary vitamin C include citrus fruits and juices,
such as oranges and grapefruit, potatoes, tomatoes, broccoli, red peppers, and cooked
collard and mustard greens.
322
[29]
prevent initiation of detectable lipid peroxidation by aqueous peroxyl radicals. For this
reason, vitamin C has been referred to as the first line of defense and has been
identified as a scavenger of several radicals.
[29]
[29]
[35]
Ascorbate reacts rapidly with both superoxide and peroxyl radicals and even more rapidly
with hydroxyl radicals.
It also scavenges singlet oxygen, reduces thiol radicals, and
combines rapidly with hypochlorous acid at sites of inflammation. Vitamin C is also
believed to have a role in sparing or recycling of alpha-tocopherol (vitamin E)
and
has been shown to spare carotenoids in vitro. It plays a vital role in maintaining the
balance between oxidative products and the various cellular antioxidant defense
mechanisms. The interdependency of such reactions involves ascorbic acid, vitamin E,
selenium, catalase, and glutathione. It is known that ascorbate can switch from anti- to
pro-oxidant activity, depending on its concentration and the presence of free transition
metal ions
; however, in plasma, transition metal ions are tightly bound and
unavailable for free radical reactions.
[13] [21]
[58] [73]
[73]
[19]
The antioxidant protection afforded by ascorbate does not correlate linearly with its
concentration in the presence of unrestricted intake. With increasing concentrations of
ascorbate, its efficiency for scavenging free radicals declines. Data from the work of Frei
et al suggest that an increase in the RDA for ascorbate from the current 60 mg to
approximately 150 mg (to maximize the total body pool of ascorbate) would be beneficial
to human health.
[29]
[21]
Ascorbate has been shown to have a major influence on phagocyte mobility and
chemotaxis. Before particle ingestion, phagocytes exhibit a marked increase in
metabolic activity known as the respiratory burst. Oxygen consumption is greatly
increased and much of this extra oxygen
[21]
323
is converted to reactive oxygen metabolites. The ROS are released into the phagosome to
be used for killing phagocytosed microorganisms; however, ROS are also released to the
exterior of the cell, where they may damage adjacent normal tissue.
[76]
Data from guinea pigs (which, like humans, do not synthesize vitamin C) have suggested
that vitamin C intake is a critical factor in the development of the immune response.
These models confirm the role of vitamin C in phagocyte cell function and suggest
effects on cytokine production.
[76]
[21] [72]
[21]
[5]
[69]
[69]
[13] [29]
[71]
VITAMIN E (alpha-TOCOPHEROL)
Dietary vitamin E includes the tocopherols--alpha, beta, gamma, and delta--and the
tocotrienols, whose most important chemical characteristic is their
324
scavenging free radicals that contain oxygen, vitamin E seems to protect cellular and
subcellular membranes from damage. In the absence of vitamin E, free radicals catalyze
peroxidation of the PUFAs that constitute structural components of tissue membranes.
The requirement for vitamin E depends on the amount of PUFA consumed, which varies
widely among individuals. Seed oils, particularly wheat germ oil, are the richest source of
vitamin E, although lesser amounts occur in fruits, vegetables, and animal fats. Peanut,
olive, coconut, and fish oils are poor sources of the vitamin.
Vitamin E as an Antioxidant
Vitamin E is a fat-soluble vitamin with a highly flexible structure, facilitating its
antioxidant function. The hydrophobic terminal of the vitamin can attach in the lipid
bilayer of the cell membrane. The terminal with a hydroxylated aromatic ring can then be
located near the water-membrane interface, where it is available to donate an electron to
those atoms with unpaired orbits.
[18] [60]
Vitamin E has several isomeric structures, but alpha-tocopherol is the isomer with the
greatest biologic activity. An electron from the hydroxyl group at the active site can be
transferred, converting alpha-tocopherol to its radical form, alpha-tocopheroxyl. Unlike
the radical forms of some molecules, the alpha-tocopheroxyl radical is very stable,
because of the nature of its ring structure. The propagation of excessive free radicals by
vitamin E is controlled by oxidizing alpha-tocopheroxyl to alpha-tocopheryl quinone or
by reducing it back to its alpha-tocopherol form in the presence of vitamin C (Fig. 4) .
[18]
[57]
Figure 4. alpha-Tocopherol.
325
Vitamin E may be beneficial to the body's host defense mechanisms by preventing the
infection-induced increase in production of tissue prostaglandins from arachidonic acid.
Prostaglandin production requires an active oxygen species, and lipid peroxides can
stimulate synthesis by providing an oxygen species.
[57]
[15]
[57]
[79]
Evidence from animal models shows that vitamin E is protective against environmental
pollutants, decreases thrombosis, reduces the formation of certain carcinogens, and
enhances almost every aspect of the immune response. The resistance to infection,
specific antibody responses, splenic plaque-forming cells, in vitro mitogenic responses of
lymphocytes, reticuloendothelial system clearance, and phagocytosis all are altered by
vitamin E deficiency. Increases in tocopherol intake have a positive impact on these
processes.
[57]
Studies in humans indicate that healthy individuals eating "normal" diets show a
significant decrease in markers of cell damage, such as lipid peroxidation and pentane
output, when they supplement their diets with vitamin E.
These studies suggest that
the average diet may not provide adequate protection against free-radical damage.
[48] [75]
326
Machtey et al found that 52% of those receiving vitamin E experienced marked relief
of pain, as compared with only 1 patient (4%) in the placebo group.
[51]
VITAMIN D
The precursors of vitamin D are present in sterol fractions of animal and plant tissues in
the form of 7-dehydrocholesterol and ergosterol, respectively. Both precursors require
ultraviolet irradiation for conversion to the provitamin form (D3 , cholecalciferol, and D2 )
and both provitamins require conversion in the kidney to the metabolically active form.
The plant form is of interest primarily as a food additive (Fig. 5) .
[52]
The RDA for vitamin D is 10 mug (400 IU) for children beyond 6 months of age, young
adults up to 25 years of age, and pregnant and lactating women. For adults 25 years and
older, the RDA is 5 mug. The normal adult is presumed to obtain sufficient vitamin D
from exposure to sunlight and the incidental ingestion of small amounts in foods.
Because vitamin D is fat soluble, hypervitaminosis D can occur from excess consumption
of supplements, including fish oils.
[52]
327
It has been shown that cultured chondrocytes convert vitamin D to its active forms.
Fairney et al found significant amounts of 25-OH-D and 24, 25-(OH)2 -D in samples of
synovial fluid from patients with OA and rheumatoid arthritis (RA). Serum levels of 25OH-D were, on average, twice as great as those in synovial fluid from the same patient.
The investigators suggested that the composition of synovial fluid is consistent with it
being a dialysate of plasma into which hyaluronan is secreted by the synovial membrane.
Therefore, the presence of vitamin D metabolites in synovial fluid may simply reflect the
serum values. In contrast, analyses of 24, 25-(OH)2 -D in samples of synovial fluid and
serum suggested local production of that metabolite in the synovium, rather than only
diffusion into the joint space from serum. No differences were noted between results of
assays of synovial fluid from patients with OA and those with RA.
[25] [31]
[25]
It is not surprising that vitamin D intakes or serum levels correlate with progression of
knee OA, because both are well-known phenomena correlated with the aging process. It
is surprising, however, that including measures of bone mineral density in statistical
models did not alter the association between vitamin D and OA, especially when the
investigators suggested that bone status was a potential mechanism through which
vitamin D might influence the progression of OA.
Defining whether investigators are describing the initiation or progression of OA is vital
to the interpretation of this association between vitamin D and OA. It has been observed
for a while now that individuals with OA are more likely to have greater bone mineral
density (BMD), and that they had that higher BMD before their presentation with
radiographically defined OA. Adequate vitamin D status, either as a result of dietary
intake or appropriate sunlight exposure, is typically a component of normal BMD, but
has not been described as a component of higher BMD. Thus, it is consistent that the
Framingham investigators
incident OA.
[55]
328
This study, which has stimulated much interest from practitioners and patients, in truth
merely highlights the need to study the role of nutrition with a clear sense of the
multifactorial nature of OA and the multiple roles that a specific nutrient may have in
cellular physiology.
Vitamin D, the Immune Response, and Osteoarthritis
One possible explanation for the role vitamin D may have played in the progression of
OA among the Framingham study subjects lies in vitamin D's potential to contribute to
the immunologic response to inflammatory products. Progression of OA associated with a
chronic and insidious inflammatory state has not been investigated relative to vitamin D,
but studies from the other more inflammatory arthritides may be informative. Peripheral
blood lymphocytes and synovial fibroblasts from patients with rheumatoid arthritis
possess specific receptors for 1, 25-(OH)2 -D, although the role of the metabolite in these
cells is unknown. Studies of the extrarenal metabolism of 25-(OH)-D show that 1, 25(OH)2 -D is synthesized in vitro by normal human macrophages activated with interferon
gamma or bacterial lipopolysaccharides. Hayes et al have speculated that activated
macrophages in patients with arthritis synthesize 1, 25-(OH)2 -D within the affected
joints. These investigators examined synovial fluid samples from 45 patients with knee
effusions and showed that synovial fluid cells were capable of synthesizing the active
vitamin D metabolite 1, 25-(OH)2 -D and that activated macrophages appeared to be
responsible for much of the 1, 25(OH)2 -D synthesized. Although the significance of the
ability of macrophages from patients with inflammatory arthritis to synthesize 1, 25(OH)2 -D is not clear, Hayes et al speculate that the importance may be greater when
the cells are present within the synovial membrane, and thus adjacent to the sites of tissue
damage and bone erosion within the joint, than when they are present in the synovial
fluid.
[41]
[46]
[65]
[41]
[41]
[74]
[66]
[31]
[41]
Vitamin D plays multiple roles that ultimately may have an effect in OA. The hormonal
form of vitamin D (1, 25-(OH)2 -D) inhibits collagen
329
[40]
[41]
SUMMARY
There are at least four mechanisms whereby the nutrient vitamins A, C, D, and E may be
related to the processes that impede or give rise to OA. These nutrient vitamins have
major roles in modulating oxidative stress, participating in immune responses, and
contributing to cell differentiation. There is a substantial need to understand the
contribution of these nutrients to OA, because they may provide important insight into
ameliorating the initiation and progression of the disease. Simultaneously, greater
understanding will add rationality to an area of potential intervention that is often based
on anecdote.
Investigation will be complex; there is the need to select appropriate systems. Typical
animal model systems used in the study of OA are inappropriate because most animals
can synthesize ascorbic acid. There is the need to disaggregate, as much as possible, the
numerous subsets of OA and the plethora of processes that contribute to that
heterogeneity. Certainly, there is the need to recognize the interdependency of the actions
of each of these nutrients at the cellular level. Furthermore, humans rarely consume these
nutrients as independent products. For example, watermelon is a primary source of both
ascorbic acid and beta-carotene. Failure to address these complexities denies the scientist
the opportunity to advance our understanding of health and disease processes. More
importantly, failure to address these complexities denies the person with OA the
opportunity to address his or her own health.
References
1. Abe
M, Newmark H, Miller G: Oral beta-carotene can increase the number of OKT4 positive cells
in human blood. Immunology 9:221, 1985
3.
330
Ali SY, Evans L: Enzymatic degradation of cartilage in osteoarthritis. Federation Proceedings 32:1494,
1973
4. Ali
R, Dosthuizen R, Maritz R, et al: The effect of increasing weekly doses of ascorbate on certain
cellular and humoral immune functions in normal volunteers. Am J Clin Nutr 33:71, 1980 Abstract
6. Bar-Shavit
Z, Teitlebaum SL, Reitsma P, et al: Induction of monocytic differentiation and bone resorption
by 1, 25-Dihydroxyvitamin D3 . Proc Natl Acad Sci USA 80:5907, 1983 Abstract
7. Barber
AA, Bernheim F: Lipid peroxidation: Its measurement, occurrence, and significance in animal
tissues. Advances in Gerontology Research 2:355-403, 1967
8. Bates
EJ, Lowther DA, Handley CJ: Oxygen free-radicals mediate an inhibition of proteoglycan synthesis
in cultured articular cartilage. Ann Rheum Dis 43:462, 1984 Abstract
9. Bendich
A: Beta-carotene and the immune response. Proc Nutr Soc 50:263, 1991 Citation
10. Bendich
11. Bendich
12. Bendich
A, Shapiro SS: Effects of beta-carotene and canthaxanthin on immune response of the rat. J
Nutr 116:2254, 1986 Abstract
13. Block
G, Menkes M: Ascorbic acid in cancer prevention. In Moon TE, Micozzi MS (eds): Nutrition and
Cancer Prevention: Investigating the Role of Micronutrients. New York, Marcel Dekker, 1989, p 341
14. Bollet AJ,
Bonner WM, Nance JL: The presence of hyaluronidase in various mammalian tissues. J Biol
Chem 238:3522, 1963
15. Boogaerts
MA, Van de Brock J, Deckmyn H, et al: Protective effect of vitamin E on immune triggered
granulocyte mediated endothelial injury. Thromb Haemost 51:89, 1984 Abstract
16. Bowman
TA, Goonewardene IM, Pasatiempo AM, et al: Vitamin A deficiency decreases natural killer
cell activity and interferon production in rats. J Nutr 120:1264, 1990 Abstract
17. Burkhardt
GW: Vitamin E: Antioxidant activity, biokinetics, and bioavailability. Ann Rev Nutr 10:357,
1990
19. Burton-Wurster
OD, Ladenbauer-Bellis IM, Panjabi M: The relationship of mechanical trauma and the early
biochemical reactions of osteoarthritic cartilage. Clin Orthop 161:275, 1981
21. Cunningham-Rundles
Maestro RF: An approach to free radicals in medicine and biology. Acta Physiol Scand 492:153,
1980
23. DeLuca
24. Dendrick
DK, Goldstein SA, Brandt KD, et al: A longitudinal study of subchondral plate and trabecular
bone in cruciate-deficient dogs with osteoarthritis followed up for 54 months. Arthritis Rheum 36:1460,
1993 Abstract
25. Fairney
A, Straffen AM, May C, et al: Vitamin D metabolites in synovial fluid. Ann Rheum Dis 46:370,
1987 Abstract
26. Freeman
B: Proceedings of a symposium: Health promotion and disease prevention: The role of antioxidant
vitamins. Discussion. Am J Med 97(suppl 3A):22S, 1994 Abstract
28. Frei
B: Reactive oxygen species and antioxidant vitamins: Mechanisms of action. Am J Med 97(suppl
3A):5S, 1994 Abstract
29. Frei
B, England L, Ames BN: Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl
Acad Sci USA 86:6377, 1989 Abstract
30.
331
Frei B, Stocker R, Ames BN: Antioxidant defenses and lipid peroxidation in human blood plasma. Proc
Natl Acad Sci USA 85:9748, 1988 Abstract
31. Garabedian
M, Lieberherr M, N'Guyen TM, et al: The in vitro production and activity of 24,25dihydroxycholecalciferol in cartilage and calvarium. Clin Orthop 135:241, 1978
32. Goetzl
EJ: Vitamin E modulates lipoxygenation of arachidonic acid in leukocytes. Nature 288:183, 1980
Abstract
33. Greenwald
RA, Mox WW: Inhibition of collagen gelation by action of the superoxide radical. Arthritis
Rheum 22:251, 1979 Abstract
35. Halliwell
B: Antioxidants and human disease: A general introduction. Nutr Rev 55(Suppl):S44, 1997
Citation
36. Halliwell
B, Aruoma OI: DNA damage by oxygen-derived species: Its mechanism and measurement in
mammalian systems. FEBS Lett 281:9, 1991 Abstract
37. Halliwell
B, Gutteridge JM, Cross CE: Free radicals, antioxidants, and human disease: Where are we
now? J Lab Clin Med 119:598, 1992 Citation
38. Halliwell
B, Gutteridge JMC: Free Radicals in Biology and Medicine. Clarendon, Oxford, 1985
39. Hamerman
40. Haussler
MR, Donaldson CA, Allegretto EA, et al: New actions of 1,25-Dihydroxyvitamin D3 : Possible
clues to the pathogenesis of postmenopausal osteoporosis. In Christiansen C, Arnaud CD, Nordin BEC, et
al (eds): Osteoporosis. Copenhagen International Symposium on Osteoporosis, June 3-8, 1984, pp 725-736
41. Hayes
ME, Denton J, Freemont AJ, et al: Synthesis of the active metabolite of vitamin D, 1,25(OH) 2 D3 ,
by synovial fluid macrophages in arthritic diseases. Ann Rheum Dis 48:723, 1989 Abstract
42. Henrotin
JA, Linn S: DNA damage and oxygen radical toxicity. Science 240:1302, 1988 Abstract
45. Kaiki
HP, Reichel H, Bishop JE, et al: Gamma-interferon stimulates production of 1,25dihydroxyvitamin D3 by normal human macrophages. Biochem Biophys Res Commun 127:596, 1985
Abstract
47. Leibovits
BE, Siegel BV: Aspects of free radical reactions in a biological system: Aging. Journal of
RF, Carlson CS, McGee MP: Expression of beta1 integrins by cultured articular chondrocytes
and in osteoarthritic cartilage. Exp Cell Res 217:248, 1995 Abstract
50. Machlin
LJ, Bendich A: Free radical tissue damage: Protective role of antioxidant nutrients. FASEB
1:441, 1987
51. Machtey
LK, Escott-Stump S (eds): Krause's Food, Nutrition, and Diet Therapy, ed 9. Philadelphia, WB
Saunders, 1996, p 85
53. Mankin
HJ, Brandt KD: Pathogenesis of osteoarthritis. In Kelley WN, Harris ED Jr, Ruddy S, et al (eds):
Textbook of Rheumatology, ed 4. Philadelphia, WB Saunders, 1993
54. McAlindon
T, Felson DT: Nutrition: Risk factors for osteoarthritis. Ann Rheum Dis 56:397, 1997
Citation
55. McAlindon
TE, Felson DT, Zhang Y, et al: Relation of dietary intake and serum levels of vitamin D to
progression of osteoarthritis of the knee among particpiants in the Framingham study. Ann Intern Med
125:353, 1996 Abstract
56. McCord
JM: The superoxide free radical: Its biochemistry and pathophysiology. Surgery 94:412, 1983
Abstract
57. Meydani
332
S (ed): Nutrient Modulation of the Immune Response. New York, Marcel Dekker, 1993, p 223
58. Niki
E, Yamamoto Y, Takahashi M, et al: Free radical-mediated damage of blood and its inhibition by
antioxidants. J Nutr Sci Vitaminol (Tokyo) 34:507, 1988 Citation
60. Packer
L: Protective role of vitamin E in biological systems. Am J Clin Nutr 53:1050S, 1991 Abstract
61. Parker
RS: Carotenoids in human blood and tissues. J Nutr 119:101, 1989 Abstract
Taylor CE, Ross AC: Vitamin A status and the immune response to pneumococcal
polysaccharide: Effects of age and early stages of retinol deficiency in rats. J Nutr 121:556, 1990
63. Peterkofsky
P, Planas JM: Synovial fluid degradation induced by free radicals. Biochem Pharmacol
27:535, 1978 Citation
65. Reichel
H, Koeffler P, Bishop JE, et al: 25-Hydroxyvitamin D3 metabolism by lipopolysaccharidestimulated normal human macrophages. J Clin Endocrinol Metab 64:1, 1987 Abstract
66. Reichel
68. Schalkwijk
J, Van Der Berg WB, Van De Putte LB, et al: Hydrogen peroxide suppresses the
proteoglycan synthesis of intact articular cartilage. J Rheumatol 12:205, 1985 Abstract
69. Schwartz
ER, Adamy L: Effects of ascorbic acid on arysulfatase activities and sulfated proteoglycan
metabolism in chondrocyte cultures. J Clin Invest 60:96, 1977 Abstract
70. Schwartz
ER, Leveille CR, Stevens JW, et al: Proteoglycan structure and metabolism in normal and
osteoarthritic cartilage of guinea pigs. Arthritis Rheum 24:1528, 1981 Abstract
71. Schwartz
ER, Oh WH, Leveille CR: Experimentally induced osteoarthritis in guinea pigs: Metabolic
responses in articular cartilage to developing pathology. Arthritis Rheum 24:1345, 1981 Abstract
72. Ten
State Nutrition Survey in the United States 1968-1970. US Center for Disease Control, US
Department of Health, Education and Welfare Publication No. (HSM) 72-8132, 1972
73. Thomas
WB, Holt PG: Vitamin C and immunity: An assessment of the evidence. Clin Exp Immunol
32:370, 1978 Abstract
74. Tsoukas
RR, Earnest DL, Prabhala RH: Retinoids, carotenoids, macrophage activation. In CunninghamRundles S (ed): Nutrient Modulation of the Immune Response. New York, Marcel Dekker, 1993, p 63
77. Watson
RR, Prabhala RH, Plezia PM, et al: Effects of beta-carotene on lymphocyte subpopulation in
elderly humans: Evidence for a dose response relationship. Am J Clin Nutr 53:90, 1991 Abstract
78. Watson
79. Yoshikawa