| Arthritis
Reimagined as Oxidative Stress
by Buck Levin, Ph.D., R.D.
How sports nutrition views the paradoxical
role of oxygen in the life of healthy joints
Oxidative stress is probably not the first thing that comes to mind when you hear the
word "arthritis." When people start talking about pain in their joints, current
wisdom implicates aging, wear and tear, physical injury or maybe even food allergies. In
sports nutrition, however, musculoskeletal injury accounts for the majority of all
injuries. What sports nutrition has shown us is that oxidative stress is key to
understanding musculoskeletal and joint health.
The Structure Of Joints
Joints, also referred to as articulations, are places where bones come together to allow
coordinated movement. They sound simple, but they aren't. There are 206 bones in the human
skeleton and the vast majority of them come together in synovial joints, where a cavity
filled with fluid separates the bones from each other. The synovial cavity is lined with a
membrane that holds the synovial fluid in place. This membrane rests not against bone, but
against cartilage, a special tissue at the ends of the bones. Because this cartilage forms
the articular surface, it is called articular cartilage.
In osteoarthritis, the most common form of arthritis, damage to the articular cartilage is
visible upon X-ray. In fact, researchers have predicted that one-third of all adults in
the United States over age 65 would show articular cartilage damage in their hands, feet,
knees amd hips upon X-ray.1 In rheumatoid arthritis, the second most common
form, the articular cartilage is compromised initially by an abnormal tissue (called
pannus) that covers the articular cartilage. Pannus develops when the joint, beginning at
the synovial membrane and working its way outward toward the articular cartilage, becomes
inflamed and damaged. Although no one is exactly sure how joint components become
dysfunctional, more and more evidence suggests that oxidative stress exacerbates
inflammation and worsens joint health.
Again, sports nutrition has taught us a great deal about oxygen, oxidative stress and
joints. Movement requires oxygen, and exercising cells may need 15 times as much oxygen as
resting cells.2 But there are paradoxes of oxygen metabolism and the process is
delicately balanced. For example, our bodies are much more efficient at producing energy
when oxygen is abundant; however, when it is, highly reactive molecules (reactive oxygen
species or ROS) are formed that can damage cells. To handle ROS, special oxygen-processing
enzymes and ROS-neutralizing molecules are required. Free radicals are one type of ROS
that requires special neutralizing molecules called "free radical scavengers."
Oxidative stress is defined as any condition in which increased ROS is not properly
balanced by increased oxygen-processing enzymes and ROS-neutralizing molecules.
The Oxidative Stress Link
One theory about the role of oxidative stress in joint pain emphasizes movement and blood
flow. Articular cartilage is unique because it is avascular, meaning it does not directly
receive blood flow. Like some other body tissues (lymphatic tissue, for example),
cartilage depends directly on movement for nourishment. Motion of the ligaments
(bone-to-bone connectors) and tendons (bone-to-muscle connectors) surrounding a joint
facilitates nutrient delivery to the cartilage in part by allowing nearby blood vessels to
fully dilate. As long as pressure in the exercising blood vessels exceeds pressure in the
synovial cavity, joint nourishment is enhanced. But when movement is absent and the
synovial pressure becomes greater than the pressure in nearby blood vessels, the vessels
can collapse and a process called hypoxic-reperfusion injury may begin.3
This process involves one of the great ironies of oxygen metabolism: ROS production and
risk of cell damage is greatest when oxygen concentrations are lowest. It seems
logical that, as more and more oxygen is delivered to a cell, the cell would be more
susceptible to damage by oxygen-related metabolism. However, the exact opposite appears to
be true. When cells are deprived of oxygen, they seem at greater risk of oxygen-related
damage than when supplied with ample oxygen. One study shows that in rheumatoid arthritis,
synovial cavity damage correlates with fluctuating oxygen pressure in the joint,
overproduction of ROS, and a lack of oxygen-processing enzymes and free radical-scavenging
molecules.4
Another theory involves the nature of connective tissue itself. Unlike most other tissues,
connective tissue is predominantly noncellular and is primarily composed of an
extracellular matrix (ECM). Three basic components are found in this ECM: fibers
(especially collagen fibers), ground substance (composed of glycosaminoglycans and
glycoproteins), and fluid.
The best-studied fibers in the ECM of connective tissue are collagen fibers. They are the
most abundant proteins in the body and constitute about 30 percent of all body protein by
weight. Collagen stability is highly sensitive to inflammatory messenger molecules such as
interleukin-1 or tumor necrosis factor alpha in the synovial fluid. When levels of these
inflammatory messaging molecules are high, collagen damage and arthritis risk are greatly
increased.5
Many forms of arthritis are significantly more common in women than men, and some
researchers think estrogen may be involved--particularly as an immune response activator.
Such a suggestion is in keeping with the findings of immune-system-related flare-ups
during times of increased estrogen metabolism; for example, flare-ups of the disease lupus
erythematosus during pregnancy. Such findings make some doctors question whether women
with this immune disorder should take estrogen under any circumstance. At the same time,
however, other immune-related diseases--such as rheumatoid arthritis--often improve during
pregnancy, thus greatly complicating the clinical picture.
Researchers from the University of Göteborg, Sweden, recently demonstrated that one form
of estrogen (estradiol) greatly suppresses collagen damage in cell cultures. It apparently
works by modifying oxidative metabolism and lowering nitric oxide production.6
Nitric oxide is a recently discovered and unique type of messaging molecule that plays a
variety of roles in the nervous and immune systems. When produced in excess it can have
damaging effects in both systems.
If the oxidative stress/connective tissue hypothesis is correct, then supplementation with
oxygen-processing enzymes and free radical-scavenging molecules should protect connective
tissue. The jury is still out, but the evidence is pointing toward a favorable verdict.
Research shows that the antioxidant n-acetylcysteine (NAC) suppresses inflammatory
messenger molecules and blocks inflammatory cascades that can result in the overproduction
of ROS. Some similar effects have been shown for the reduced form of the antioxidant
glutathione (GSH), and also for the oxygen-processing enzyme catalase (CAT).7
Interestingly, cell culture research conducted at Rush Medical College in Chicago showed
no protective results for the better-known protective enzyme superoxide dismutase (SOD).8
In these same studies, researchers emphasized that antioxidant protection only seems to
work in conjunction with the body's immune messaging systems. In other words, the
antioxidants may not be working directly on the damaged cartilage and connective tissue
but may instead be shifting cytokine balance. Cytokines--protein hormones produced by
immune cells--are the messaging molecules of the immune system that help regulate immune
and inflammatory processes. Cytokines include molecules called interferons and tumor
necrosis factors.
If this theory is correct and connective tissue damage is "cytokine driven,"
future research might focus more specifically on known modifiers of cytokine balance,
including branched-chain amino acids, sulfur-containing amino acids, many carotenoids,
vitamin E, essential fatty acids, isoflavones such as those found in soybeans, lipoic
acid, curcumin (in the spice turmeric) and other phytochemicals from beverages like green
tea, or culinary herbs like rosemary (Rosmarinus officinalis).
Glycosaminoglycans' Role
Two major families of molecules are present in the ground substance of connective
tissue--glycosaminoglycans (GAGs) and glycoproteins. Sometimes GAGs are referred to as
mucopolysaccharides.
In addition to their critical role in determining the structure, viscosity and
permeability of the ground substance in connective tissue, GAGs play important metabolic
roles in connective tissue and joint health. Ion transport, nutrient diffusion, water
retention, growth-factor binding, intercellular signaling and collagen synthesis all
depend on GAG function.9
Hyaluronic acid (HA), which contains glucosamine and glucuronic acid, is a critical GAG in
synovial joints because it is the predominant GAG in the articular surface and also is a
key component of the synovial fluid. Orally supplemented glucosamine is shown to be
readily incorporated into hyaluronic acid synthesized by fibroblast cells.10
This research suggests that the ability of joint cells to keep the connecting surfaces of
the bones in top condition may be enhanced by glucosamine supplementation. Availability of
glutamine appears to be an important factor in the manufacture of glucuronic acid, the
other key component of HAs.
Oral supplementation with glucosamine sulfate has been examined in numerous studies of
osteoarthritis with repeatedly impressive results. Daily dose ranges have varied between
750 and 1,500 mg, usually administered in three to six equally divided amounts. Compared
to nonsteroidal anti-inflammatories like ibuprofen, glucosamine sulfate is slower acting
but more effective over an eight-week period.11 In Portugal, a large
multicenter trial involving 252 physicians and 1,208 arthritic subjects found oral
glucosamine was more effective in reducing pain from exertion and decreasing limitations
on active and passive movement than all other treatments except glucosamine injection.12
The exact connection between GAGs and oxidative stress is not entirely clear. We know that
the end surfaces of the bones where they meet in a joint require the ample and intact
presence of hyaluronic acid. We also know that HA can be damaged by reactive oxygen
molecules. These molecules multiply when parts of the body are temporarily deprived of
oxygen and then re-oxygenated (a process called hypoxia-reperfusion).13
Studies of endothelial tissue in the lungs show there is a decrease in cellular
proteoglycans (GAGs linked together) upon exposure to oxidized fats. The decrease is
caused by dysfunction in proteoglycan metabolism.14 If similar mechanisms are
at work in the joint, many of the considerations involving oxidized lipids, plaque
formation and atherosclerosis--which we have been considering primarily in the area of
cardiovascular health--will become considerations in understanding arthritis as well.
Essential Fatty Acids
Essential fatty acids (EFAs) are critical in regulating oxidative stress and joint
inflammation. The kinds of fat in the diet, in particular the ratio of omega-3 to omega-6
fatty acids, dramatically affects inflammation. Synthesis of pro-inflammatory messaging
molecules (made from arachidonic acid) is only inhibited when the fatty acid ratio ranges
from 1:1 to 1:2.15 It is often a good idea to inhibit synthesis of arachidonic
acid because it can be converted into several messaging molecules that encourage
inflammatory response. When too much arachidonic acid is channeled this way, chronic
inflammation can result and, in turn, damage cells and organ systems.
In the United States, the ratio of omega-3 to omega-6 fatty acids ranges from 1:10 to
1:25--exponentially higher than the worldwide average. To make matters worse, virtually
all public health recommendations in the last 10 years have created further obstacles for
a balanced ratio. Recommendations to use plant oils high in omega-6 (canola, safflower and
sunflower oil) are a blueprint for highly imbalanced fat ratios. This could be remedied if
people ate more cold-water fish such as salmon and halibut, as well as flax and pumpkin
seeds.
The list of oxidative stress-related conditions has grown steadily in the past 10 years.
Parkinson's and Alzheimer's diseases,16 atherosclerosis,17 inflammatory
bowel disease,18 lung cancer19 and AIDS20 are now joined
on the list by arthritis. While the oxidative stress connection might complicate our
approach to nutritional support for the joints, it may also simplify our understanding of
diet and health. It moves toward a unified theory of many common disorders and focuses
attention on an increasingly well-recognized group of antioxidant supplements.
Sidebars:
Joint
Glossary
References
1. "Arthritis, rheumatic diseases, and related disorders." National
Institutes of Health Publication No. 93-3413, U.S. Department of Health and Human
Services, Public Health Service, 1993.
2. Clarkson, P.M. "Antioxidants and physical performance." Crit Rev Food Sci
Nutr, 35(1-2): 131-141, 1995.
3. Mapp, P.I., Grootveld, M.C., et al. "Hypoxia, oxidative stress and rheumatoid
arthritis." Br Med Bull, 51(2): 419-436, 1995.
4. ibid.
5. Joosten, L.A., Helsen, M.M., et al. "Accelerated onset of collagen-induced
arthritis by remote inflammation." Clin Exp Immunol, 97(2): 204-211, 1994.
6. Josefsson, E. & Tarkowski, A. "Suppression of type II collagen-induced
arthritis by the endogenous estrogen metabolite 2-methoxyestradiol." Arthritis
Rheum 40(1): 154-163, 1997.
7. Sato, M., Miyazaki, T., et al. "Antioxidants inhibit tumor necrosis factor-alpha
mediated stimulation of interleukin-8, monocyte chemoattractant protein-1 and collagenase
expression in cultured human synovial cells." J Rheumatol, 23(3): 432-438,
1996.
8. Homandberg, G.A., Hui, F., et al. "Fibronectin fragment mediated cartilage
chondrolysis. II. Reparative effects of anti-oxidants." Biochem Biophys Acta,
1317(2): 143-148, 1996.
9. Ledbetter, W.B. "Cell matrix response in tendon injury." Clin Sports Med,
11(3): 533-578, 1992.
10. Prehm, P. "Hyaluronate is synthesized at plasma membranes." Biochem J,
220: 597-600, 1984.
11. Vaz, A.L. "Double-blind clinical evaluation of the relative efficacy of ibuprofen
and glucosamine sulfate in the management of osteoarthritis of the knee in
out-patients." Curr Med Res Opin, 8(3): 145-149, 1982.
12. Tapadinhas, M.J., Rivera, I.C., et al. "Oral glucosamine sulfate in the
management of arthrosis: Report on a multi-centre open investigation in Portugal." Pharmather,
3(3): 157-168, 1982.
13. Mapp, et al., loc. cit.
14. Ramasamy. S., Lipke, D.W., et al. "Oxidized lipid-mediated alterations in
proteoglycan metabolism in cultured pulmonary endothelial cells." Atheroscler,
120(1-2): 199-208, 1996.
15. Boudreau, M.D., Chanmugam,S., et al. "Lack of dose response by dietary n-3 fatty
acids at a constant ratio of n-3 to n-6 fatty acids in suppressing eicosanoid biosynthesis
from arachidonic acid." Am J Clin Nutr, 54: 111-117, 1991.
16. Beal, M.F. "Aging, energy and oxidative stress in neurodegenerative
diseases." Ann Neurol, 38: 356-366, 1995.
17. Rajman, I., Kendall, M., et al. "The oxidation hypothesis of
atherosclerosis." Lancet, 344: 1363-1364, 1994.
18. Grisham, M.B. "Oxidants and free radicals in inflammatory bowel disease." Lancet,
344: 859-861, 1994.
19. Cross, C.E., van der Vliet, A., et al. "Reactive oxygen species in the
lung." Lancet, 344: 930-933, 1994.
20. de Lorgeril, M., Richard, M-J., et al. "Increased production of reactive oxygen
species in pharmacologically-immunosuppressed patients." Chem Biol Interact, 91:
159-164, 1994.
Buck Levin, Ph.D., R.D., is associate professor
of nutrition at Bastyr University in Bothell, Wash., and cofounder of Hingepin Partners, a
producer of camera-ready health education materials.
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