University of Pittsburgh research team delves into osteoarthritis
May 6, 2014 12:00 AM
Bob Donaldson / Post-Gazette
Deborah Cole Thomas' arthritis has led to an ankle replacement and two mid-foot fusions. She works out a a gym to help her joints remain flexible.
By David Templeton / Pittsburgh Post-Gazette
Her foot pain began 15 years ago, leading to a 2002 diagnosis of osteoarthritis, which left her limping and unable to walk for extended periods of time.
And it progressively worsened.
In time, Deborah Cole Thomas, 60, of Plum, would undergo surgeries to fuse joints in both feet along with a left-ankle replacement, all from the wear-and-tear form of arthritis. She endured shoulder pain and more recent problems with right-knee pain, which she likens to a knife stab.
Round-the-clock pain medications are a must.
“I try not to let it affect me,” Ms. Thomas said, noting that her husband, Llewellyn, 82, has had both arthritic knees replaced. “It drives me to keep moving. I watched my mom give up, and her hands became so crippled she had to be fed.”
PG graphic: Solving the mystery of arthritis (Click image for larger version)
Ms. Thomas, now retired, worked as a Westinghouse computer engineer, spending hours at a desk that made her “feel like the Tin Man in ‘The Wizard of Oz.’ ” She’d stand and struggle to flex stiffened joints.
In coming years, she faces further surgeries, including knee-replacement surgery. But she’s still walking, with the goal of 10,000 steps a day and an average of about 7,000.
“I wouldn’t go to climb Mount Washington — or Kilimanjaro,” she said, adding that osteoarthritis can be immobilizing if you let it. She also can’t run and isn’t allowed to jump. Doctor’s orders. But she works around those limitations.
“There’s always something I can do just to keep moving.”
While people with osteoarthritis struggle to move, there’s plenty of movement in research as scientists work through the biological puzzle of osteoarthritis to come up with potential treatments.
A University of Pittsburgh research team, led by Rocky S. Tuan — professor and executive vice chairman of the department of orthopedic surgery and director of the Center for Cellular and Molecular Engineering — is making headway in understanding the complex stew of enzymes (histones), proteins and genes that cause osteoarthritis while identifying a potential treatment to slow the rate of cartilage destruction.
There’s further breaking news from the Tuan camp that sounds like science fiction:
His Pitt team is using a 3-D printer, which makes structures one layer at a time, to make new joints. Using a solution containing the patient’s stem cells, along with growth factors and scaffolding material, the 3-D printer constructs actual cartilage in the right shape to replace damaged cartilage.
The stem-cell solution extruded through a catheter also could be used to create new cartilage, as guided by a 3-D printer, directly onto the joint bone.
The team’s tissue-engineered joints already have shown success in large animals, raising the promise of creating replacement joints for people now dependent on plastic and metal ones. The process could be particularly useful in repairing battlefield injuries.
Mr. Tuan announced the success April 27 at the Experimental Biology 2014 scientific sessions and meeting in San Diego.
“We essentially speed up the development process by giving the cells everything they need, while creating a scaffold to give the tissue the exact shape and structure that we want,” Mr. Tuan said, adding that his team continues working to develop cartilage more closely resembling human cartilage.
“Total joint replacements involving plastic and metal joints work well, but they don’t last long enough,” Mr. Tuan said. “For someone who is 60, that’s OK. But if you are in your 30s, that’s not good because you may need revision after revision.
“We are not in position to say that it will last a lifetime. Time is the true test,” Mr. Tuan said of the tissue-engineered joints his team has created. “I can only say it’s very promising and is looking good.”
Joints, the business end of bones, include a covering made of flexible and protective cartilage to prevent damage from friction. But chronic wear and tear from overuse, traumatic injury or bone misalignment, among other factors such as obesity, promotes a biological process, not yet fully understood, that degrades cartilage.
Osteoarthritis represents 80 percent of all cases of arthritis, whose various forms plague 27 million Americans, making arthritis the nation’s major form of physical disability. The disease burden is particularly acute in the aged population, with one out of two individuals older than 65 having at least one joint affected.
In other promising Pitt research, Mr. Tuan and Veronica Ulici, an Arthritis Foundation-supported post-doctoral fellow at Pitt and medical doctor, are focusing on a method to prevent destruction of the cartilage, which would do away with the need to replace joints.
“The joint is a very interesting organ,” Mr. Tuan said. “There is no blood flow there, or nerves.”
The immune response in the joint that occurs from chronic wear and tear or injury increases the level of unhealthy inflammation, which eventually causes cartilage degradation. Mr. Tuan said, “It tries to repair itself, but in the end it fails.”
Mr. Tuan, a doctor of biochemistry and cell biology, and Dr. Ulici have investigated the process, which focused attention on the histone deactetylase enzymes, or HDAC.
Injury to the joint activates certain genes to produce known inflammatory factors, which increase the activity of degradative enzymes. Genes activated by injury can be bad ones, initiating a vicious cycle of enzyme degradation that causes fibrillation on the cartilage surface while chewing up cartilage.
The Pitt studies involving cow tissues show that injured cartilage appears to generate increased levels of HDAC enzymes, raising the specter that they play a key role in activating the changes leading to cartilage damage. But a pharmaceutical agent that inhibits HDAC, already being tested as a treatment for lymphoma, slows down the degradation of cartilage, the Pitt team has found.
As such, it holds promise as a treatment, with the advantage of already being tested for safety in human clinical trials as a lymphoma treatment. It would take five or more years before any treatment is available, if all goes well with the research.
“Once we know the effects, we can stop them with treatment,” said Dr. Ulici, a key figure in the series of studies. “If we can do that, we can prevent osteoarthritis and its changes in the tissue.”
While the pharmaceutical agent doesn’t stop cartilage degradation, “we do see good improvement,” Dr. Ulici said. “The inflammatory molecules are going down.”
“Obviously, the goal is to prevent degradation from happening in the first place,” Mr. Tuan said. “Based on Veronica’s findings, if someone gets banged up one way or another, there’s a way to make sure HDAC activity is involved, then use inhibitors that are injected to avoid degradation” of the cartilage.
There’s even more news that could advance treatments for osteoarthritis.
The Pitt team also is using tissue engineering to develop human tissue and cartilage in a laboratory dish that can be used to test the effect of drugs. The live model of human joint tissue is being heralded as the creation of “the first example of living human cartilage grown on a laboratory chip.”
For now, the engineered cartilage tissue on a computer chip will serve “as a test-bed for researchers to learn about how osteoarthritis develops” and to develop new drugs.
“We hope that the methods we’re developing will really make a difference, both in the study of the disease and, ultimately, in treatments for people with cartilage degeneration or joint injuries,” said Mr. Tuan, who also serves as director of the McGowan Institute for Regenerative Medicine and director of the Center for Military Medicine Research at the Pitt School of Medicine.
Osteoarthritis, the Arthritis Foundation website states, “leads to 632,000 joint replacements per year, with a total cost of $128 billion in 2012 for medical care and indirect expenses, including lost wages and productivity. One in two people will develop a form of arthritis in their lifetime.”
Nearly 3 million people in Western Pennsylvania have osteoarthritis, according to the foundation’s Great Lakes, Western Pennsylvania, chapter.
It is distinct from rheumatoid arthritis, an autoimmune disease that causes chronic inflammation in flexible joints, with potential to lead to severe disability if left untreated. But it affects less than 1 percent of Americans.
The foundation said trends suggest that “half of all adults will develop symptomatic osteoarthritis of the knee at some point in their lives and the risk increases with obesity to two of every three obese adults.”
Women older than 50 are more commonly affected by osteoarthritis than men, with it typically beginning after age 40.
But arthritis is a tough opponent. Ms. Thomas, as board member of the foundation’s regional chapter, says people must work to stave off immobility by walking and exercising. She’s trying to avoid another round of foot surgery. That’s why the Pitt research is stirring optimism for her and the Arthritis Foundation.
“Replacing cartilage with extra good stuff would be fantastic,” she said. “Oh, Lord, it’s exciting. I can’t wait.”
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