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Part One: Reactive Oxygen Species and Osteoarthritis

Dr. Falk: Today what we want to talk about is osteoarthritis. What is osteoarthritis?

Dr. Loeser: Osteoarthritis is by far the most common form of arthritis. It鈥檚 the type that has been associated with aging. It鈥檚 the type you see in older adults and not in children. It鈥檚 associated with the breakdown of the cartilage which is the tissue that covers the surface of the joint as well as changes within the joint lining, the synovium and the bone,sometimes called bone spurs or osteophytes. One of the misconceptions about this type of arthritis is people have called it 鈥渨ear and tear鈥� degenerative joint disease and we鈥檙e trying to get the message out that arthritis is more than just wear and tear, it鈥檚 a breakdown of the joint tissue that occurs from production of enzymes that destroy the tissue. So it doesn鈥檛 just wear away, there鈥檚 a biological process behind it.

It鈥檚 a process where enzymes are produced by the cartilage cells that are responsible for breaking down the cartilage. So rather than the tissue just wearing away, it鈥檚 a biological process, and there鈥檚 a role for inflammation in the joint, that stimulates the production of these enzymes that break down the joint tissue.

Dr. Falk: Why does this happen as I am getting older? Because it is, to a certain extent, an older-age disease.

Dr. Loeser: The processes that change in your body with age predispose you to getting osteoarthritis but then there are usually other factors that stimulate it to start. For example, injuring your joints. Say you tear your ACL or meniscus. Or people that are obese, overweight. Or there鈥檚 a genetic component as well. The aging works in conjunction with other risk factors to result in the development of osteoarthritis.

Dr. Falk: All of the sports injuries that we have, in high school and college, then come back and bite us when we鈥檙e older in the form of osteoarthritis.

Dr. Loeser: Yes, that鈥檚 a major risk factor for osteoarthritis and sometimes that鈥檚 called post-traumatic osteoarthritis to distinguish it from the osteoarthritis that鈥檚 associated with obesity or that associated with aging when there are no obvious risk factors present.

Dr. Falk: You鈥檝e mentioned the word inflammation, an inflammatory process. That can be separated from other inflammatory arthritides like the crystal arthritis- gout, or other sorts of crystals. How can one tell whether it鈥檚 osteoarthritis or whether it鈥檚 one of these crystal diseases?

Dr. Loeser: Two ways. One is the acute onset versus chronic onset of inflammation. With crystals, it鈥檚 a real acute inflammatory condition.

Dr. Falk: It happens suddenly.

Dr. Loeser: Happens suddenly, and the joint is red, hot, and swollen. With osteoarthritis, it鈥檚 much more gradual and the amount of inflammation is much less, so that you may not even perceive it from the outside of the joint, but it鈥檚 active within the joint tissues.

Dr. Falk: Sometimes osteoarthritis can look pretty inflamed.

Dr. Loeser: Yes. When it flares up, it can look more inflamed, but usually not to the same extent as a crystal-induced arthritis or rheumatoid arthritis, which is a classical form of inflammatory arthritis.

Dr. Falk: One of the things that your research has taught us is the role of what are called reactive oxygen species, and the destruction of the joint. What are these reactive oxygen species? Where do they come from and what do they do to the joint?

Dr. Loeser: Reactive oxygen species are naturally produced in all of the cells of your body, particularly in the mitochondria, where they are used to generate energy. Oxygen is important for producing ATP, the source of energy, and as a by-product of that, reactive oxygen species are produced.

But then other cells in your body, such as white blood cells, produce reactive oxygen species to kill bacteria and fight off infection. But more recently what鈥檚 been found is that reactive oxygen species are produced as second messengers in cell signaling pathways. So they鈥檙e important transducers of signals in response to stimulation by a number of factors. Growth factors and cytokines. They actually tell the cell how to respond to one of these external stimuli.

When they鈥檙e produced in excess amounts, they can do two things to the joint. They can directly damage joint tissue cells, damaging DNA, protein, lipids, but more importantly, they alter the cell signaling pathways. And that results in producing more of the enzymes that then destroy the joint.

Dr. Falk: I want to avoid the unnecessary production of reactive oxygen species. How do I do that?

Dr. Loeser: Well, the more obvious thing that hasn鈥檛 worked so far is taking antioxidants: Vitamin C, Vitamin E, and these have been studied for years with the hope that they can decrease the amount of reactive oxygen species. But they never seem to work.

They don鈥檛 seem to be specific enough for the reactive oxygen species that are actually made within the cells. And they also don鈥檛 seem to get where the action is. So their ability to penetrate inside the cell, and get to a location such as the mitochondria is very limited. The general antioxidants that are available right now just don鈥檛 seem to do the trick.

Dr. Falk: It鈥檚 really then a matter of getting the material that you鈥檝e swallowed and get it to the microenvironment to where the battle is being waged.

Dr. Loeser: Exactly. Then the other approach that seems to be more promising is to be able to induce your cells to make their own natural antioxidants. There鈥檚 a protein that鈥檚 a transcription factor, which regulates expression of genes called 鈥淣rf2.鈥� Nrf2 turns on the production of antioxidant enzymes by your cells. If you can stimulate your cells to make their own antioxidants, then they鈥檙e going to be available more locally inside the cells to do what they need to do to reduce the level of ROS.

Dr. Falk: There are a number of ways, theoretically, of turning on transcription factor. How would one do it in practice?

Dr. Loeser: In practice, I would have to say that we鈥檙e not quite there yet, in terms of having a drug that will do that. That鈥檚 an area of active investigation. The hope is that we will be able to develop that.

Part Two: Prevention and Treatment of Osteoarthritis

• What are effective treatments for osteoarthritis?
• How do you treat arthritis in the hands?
• How do you prevent osteoarthritis?
• What is the future of your research in reactive oxygen species?

Dr. Falk: If you鈥檙e taking care of a patient with osteoarthritis, do you use antioxidants? Do you use anything in the hopes of stimulating Nrf2, the 2 sides of that equation?

Dr. Loeser: Not yet, we don鈥檛 have something that we know will do that. In terms of dietary factors, we still recommend a healthy, well-balanced diet, figuring that a combination of vitamins and minerals in your diet will have some benefit, rather than say a single, particular factor you would take over the counter.

Dr. Falk: If you had osteoarthritis, how would you treat it? Let鈥檚 say it鈥檚 your knee, it just slows you down.

Dr. Loeser: The drugs that are available right now, they are fairly good at helping to control pain. But they don鈥檛 really affect the disease progression.

Dr. Falk: Nonsteroidal or anti-inflammatory drugs.

Dr. Loeser: Nonsteroidals will definitely help reduce pain, but then, of course, they have side effects. You can get just about as much benefit by doing exercises. So by strengthening the muscles that help support the joint, you can get just as much pain relief, plus more improvement in function than you can by taking nonsteroidals.

Dr. Falk: You鈥檙e telling me that I should exercise more of the muscles around my knee, because that鈥檚 going to help the osteoarthritis, even though it hurts when I鈥檓 doing it?

Dr. Loeser: Yes. You have to gradually build up the exercises so you can tolerate it. But the muscles are helping to control the load that鈥檚 put on your joint. The cartilage that鈥檚 in your joint doesn鈥檛 absorb any shock鈥攊t鈥檚 the muscles, bone, that are really absorbing the joint loads. So by strengthening the muscles, you lower the amount of load on the rest of the joint.

Dr. Falk: That requires at least a gradual approach of muscle strengthening, in some sort of organized exercise program. We wouldn鈥檛 want the average listener to suddenly start exercising and hurt themselves.

Dr. Loeser: Right. I鈥檝e been involved in several kinds of exercise studies now. What we鈥檝e learned is that learning the right exercises, and having a physical therapist, or an exercise specialist teach you the exercises and watch you do them correctly is really important to be able to do them safely and build up your muscles adequately.

Dr. Falk: What happens in the hands? So many people have real joint complaints in the hands. How do you exercise your hand?

Dr. Loeser: There are some exercises for hands. Squeezing tennis balls, and other types of devices. But you鈥檙e right, that鈥檚 more limited in terms of what you might be able to do for other muscles such as the ones that are around your knee joint.

Dr. Falk: The thought had been that one should mold clay, that clay was helpful. Is that right? Is that just a hand exercise?

Dr. Loeser: It can help reduce stiffness in your hands by doing that type of motion. But in terms of how much it strengthens muscles it doesn鈥檛 seem to have that much effect on the muscles themselves.

Dr. Falk: How do you prevent osteoarthritis? Obviously you would like to prevent traumatic injury. Sounds like losing weight would be equally important to prevent obesity-induced joint disease. What else can one do to prevent osteoarthritis?

Dr. Loeser: As you mentioned, weight loss for people who are overweight, and that鈥檚 been shown to prevent the development of osteoarthritis. And then exercising and keeping your muscles strong because your muscles really help to support your joint, so if you stay in shape and keep your muscles strong, there鈥檚 some evidence that that can help prevent osteoarthritis as you get older.

Dr. Falk: Let鈥檚 talk about this form of exercise. Running versus walking, treadmills versus an ellipse, marathons or Ironmans? What鈥檚 the recommendation?

Dr. Loeser: The recommendation really depends on your individual joints. If you鈥檙e healthy, with healthy joints, you can run marathons and there鈥檚 no evidence that it damages your joints. There have been some really well-done studies in older adults who have run marathons for 20 years and they actually have less osteoarthritis than people of the same age who don鈥檛 run. There鈥檚 this misconception that years of running will destroy your joint and cause arthritis. That鈥檚 not true, if you have normal joints.

If you鈥檝e injured your joints, torn your ACL, torn your meniscus, and then you run on that joint, that鈥檚 when you鈥檙e in trouble for getting osteoarthritis. The type of exercise that you do really depends on your individual joint. If you鈥檝e never had a joint injury and you鈥檙e healthy, weight-bearing exercises are great.

If you鈥檝e injured your joint before, then something like the elliptical or water exercises are probably safer.

Dr. Falk: Let鈥檚 take the more common reality of someone who is out of shape who is now trying to get into shape and hasn鈥檛 been a long-term walker. What do you tell them to do? Gradually increase the amount of exercise?

Dr. Loeser: Right, gradually increase it as they tolerate it. It鈥檚 probably better to exercise every other day so that you give your muscles a day to adapt and rest up, rather than every day exercises seem to cause more muscle break-down. And then having some type of instruction doing correct exercises is a lot of help as well.

Dr. Falk: Let鈥檚 come back to the work that you鈥檝e been doing with reactive oxygen species. Where do you think all that鈥檚 going to go? What should we look out for in the future?

Dr. Loeser: I think we鈥檙e going to be able to learn how to target the effects of reactive oxygen species in terms of the cell signaling. It鈥檚 really the alteration in cell signaling that鈥檚 driving the joint tissue breakdown. Developing new inhibitors that target those specific processes are going to be most promising for treating arthritis.

Dr. Falk: Thank you so much for spending time with me today, Dr. Loeser. We look forward to hearing all about your studies as they unfold.

Dr. Loeser: You鈥檙e welcome.

Dr. Richard Loeser is the Herman and Louise Smith Distinguished Professor of Medicine in the Division of Rheumatology, Allergy, and Immunology, and is Director of Basic and Translational Research in the Thurston Arthritis Research Center.

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