Joint Disease Research

It was the Belmont Stakes, third race in the Triple Crown, and the year was 1999. A big, strapping, chestnut colt had come from nowhere to surprise the racing world with victories in the Kentucky Derby and Preakness. His name, fittingly, was Charismatic. Now, he only needed a victory over the 11⁄2-mile distance of the Belmont to win the Triple Crown and $5 million in bonus money. It started out well enough, but it didn't finish that way. Charismatic crossed the finish line third and then stumbled. No one who saw it will forget the heartrending sight of jockey Chris Antley leaping to the ground and lifting the colt's left foreleg, holding it aloft to avoid further damage to bones and tissues.

There had been a fracture. There would be a happy ending of sorts. A 2.5-hour operation would save Charismatic's life. He would never race again, but he would be plenty fit for stud duty.

Switch sports and locales. A National Football League running back takes the handoff from his quarterback. A beefy offensive tackle and an equally hefty offensive guard open a gaping hole. The running back shoots through it, cutting left to avoid the onrushing linebacker, cuts back to the right, and goes down as he is met by a safety. Instead of scrambling to his feet, the running back writhes on the ground in agony. Trainers rush to his aid and he is helped from the field, supported by the shoulders of a teammate and trainer. It is later announced he has suffered a severe knee injury.

What do these two injuries have in common? Plenty.

Scientific researchers have learned that the injuries suffered by human and equine athletes, especially as they relate to joints, often are very similar. Now, they are using that knowledge in their attempts to find ways to prevent injuries to both.

Four of the research institutions--there are others--where equine and human research are intertwined are Colorado State, Michigan State, Cornell, and Ohio State Universities.

Some of the most ambitious research is being conducted at Colorado State (CSU), where a new Orthopaedic Research Center just opened its doors. Director of the center is Dr. Wayne McIlwraith, recently named the Barbara Cox Anthony University Chair in Orthopaedics.

It is only logical there be a crossover of human and equine research, McIlwraith said, because there are so many similarities with their joints and the stresses that are placed on them in athletic competition.

The human/equine research crossover is at least partially attributable to CSU's connections with the Steadman-Hawkins Sports Medicine Foundation. The foundation carries the name of two renowned orthopedic surgeons who operate a clinic in Vail, Colo. The player in the equine-human research game from the foundation is Dr. J. Richard Steadman. He is, said McIlwraith, one of the world's leading knee surgeons.

A mutual friend introduced Steadman and McIlwraith, and the two have worked together on research projects involving humans and horses ever since. Their first joint venture was to validate a micro-fracture technique Steadman had invented, one of two new procedures attributed to Steadman.

Because much of the CSU orthopedic equine research can be carried over to the human sector, the university has received several substantial grants from foundations that normally fund research on humans only. National Football League Charities, for example, contributed $200,000. The Charles Koch Foundation, also primarily interested in human research, contributed $350,000, and the Steadman-Hawkins Sports Medicine Foundation came through with another $250,000.

The combined efforts of human and equine researchers are bearing fruit. Treatment protocols are surfacing that are applicable to both species of athletes. The successes have stimulated even more combined research.

For example, McIlwraith said, one research project using gene therapy involved equine researchers from CSU and Cornell University in collaboration with researchers from the University of Pittsburgh and Harvard University who were delving into the effects of the therapy on humans.

Research into gene therapy is cutting edge, McIlwraith said, and holds great promise for both equine and human sufferers of arthritis. The conventional treatment for this condition primarily has involved anti-inflammatory medication. While the medications often reduce swelling, they do relatively little to protect the joints against further damage.

Enter Dr. David Frisbie, a researcher at the CSU Orthopaedic Research Center (officially known as the Gail Holmes Equine Orthopaedic Research Center, in honor of a major financial contributor).

Frisbie, recently honored by Pfizer Animal Health with its award for research excellence, launched a study into gene therapy that holds promise for not only improving soundness in horses-- and in humans --but for actually protecting the joint tissues in such a way that arthritis does not worsen.

It was a lengthy investigation that began with the discovery that a protein known as I1-1Ra was found in higher levels in people who had contracted and recovered from Lyme disease. One of the symptoms of Lyme disease is arthritis. This discovery served to pose the question of whether the protein could ease the joint pain associated with arthritis.

Researchers earlier had learned that another protein, this one known as Interleukin 1 (IL-1), is responsible for some of the debilitating progress of arthritis. They also learned I1-1Ra is capable of destroying Interleukin 1, much the same as antibiotics destroy harmful bacteria.

The next step involved isolating the DNA gene sequences that code for production of the two proteins. The lead researcher was Dr. Rick Howard (now at the University of Virginia) during his PhD work at CSU.

When that had been accomplished, Frisbie's challenge was to find a way in which to insert the gene sequence directly into living cells. He turned to an unlikely helper --a virus. Viruses, the CSU researchers point out, have evolved in such a way that they are able to insert their own DNA into cells of other organisms. This ability, according to the researchers, makes them a perfect vehicle for inserting foreign gene sequences into a horse's cells.

Frisbie injected a harmless virus with the I1-1Ra's DNA into joints of horses with chip fractures that had induced an arthritic condition. The virus inserted the I1-1Ra gene sequence into living cells, which made the cells adopt the DNA as their own. The cells then began producing the anti-arthritic protein.

The results had researchers ecstatic. Not only did the horses become sounder, with inflammation reduced, but the gene therapy actually halted the development of osteoarthritis. A published report on the research concluded thusly: "This has exciting implications for both horses and humans suffering from joint problems. The new gene therapy research, which is supported by the Steadman-Hawkins Foundation, hopefully will help to heal cartilage defects and further alleviate the suffering of many who are living with arthritis."

While research projects at CSU are centered on orthopedics, studies being conducted at Michigan State University under the direction of Dr. Steven Arnoczky are seeking to determine underlying causes for tendon problems suffered by both human and equine athletes. The Michigan State research, Arnoczky said, is trying to determine what happens at the molecular level when over-use injuries to equine and human tendons occur. Only after it has been learned what is happening at the molecular level can procedures and therapies be designed to prevent injury from occurring, he said.

It is believed, Arnoczky said, that excess stress produces proteins that may signal cells to destroy themselves by a process known scientifically as apoptosis. The studies now under way, he said, are designed to answer a number of questions: What role does conditioning play? At what point do cells adapt to stress to avoid destruction? Are there other ways to minimize cellular stress? At what point is training overdone? At what point is training underdone? Are tendon injuries age-related?

Arnoczky said researchers, through molecular research, are trying to find that proper window where just the right amount of training will properly prepare tendon cells for the stress of competition.

Because of the similarities in equine and human tendons, he said, the horse makes an excellent model for the research. Equine tendons involved in the research come from horses that have been euthanized for some other reason.

A part of the study, Arnoczky said, is aimed at determining what effect vigorous exercise of foals and young children might have on the potential for future tendon problems.

Dr. Alicia Bertone is working in research at Ohio State University that involves gene therapy as a modality for dealing with cartilage damage. The horse is an excellent model to relate to humans, she said, because of joint similarities. For example, she pointed out, the knee joint of the human and the carpus (knee joint of the horse) are about the same size and contain the same amount of synovial fluid. (She is quick to point out, however, that the knee joint of the human is comparable to the horse's stifle joint, which is considerably larger than the human knee joint.)

Bertone's research involves using mutant viral vectors that are unable to replicate as vehicles for delivering gene therapy directly to the joint. Bertone holds the Trueman Family Endowed Chair, which is responsible for a portion of the research program's funding.

Also conducting research that involves both humans and horses is Dr. Alan J. Nixon of Cornell University. His research focus is in chondrocyte metabolism and cartilage repair. Nixon's research group has focused on the cloning of growth factor molecules for use in gene therapy protocols, inserting the growth factor gene into cartilage cells by direct joint injection. The laboratory group also studies the molecular changes associated with osteochondritis in horses and man and investigates treatment methods for tendonitis in athletes. The Cornell researchers have collaborated with their counterparts at Colorado State.

About the Author

Les Sellnow

Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.

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