Examining the Effects of Steroids on Joint Tissue INSIDE
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Areport from the Harry M. Zweig Memorial Fund for Equine Research at the College of Veterinary Medicine at Cornell University No. 18 November 1994 Zweig support is helping Dr. James MacLeod understand howsteroids change thebiology ofjoint tissues. Examining the Effects of Steroids on Joint Tissue INSIDE ^ Dr. Ronald Minor Develops UrineTest Duringa race, thoroughbred horses pound the track with such force to Detect Bone Weakness that 12,000 pounds of pressure is exerted on the cannon bone ^ Globe-trottingOrthopedicSurgeonDr. alone. "Such physical exertion and musculoskeletal stress predisposes Alan Nixon most race horses to jointdisease that sooneror latercompromises their ^. Committee Member Profile-William careers," says Dr. James MacLeod, a veterinary molecular geneticist at Welch Cornell's College of Veterinary Medicine. In recentyears, however, manypeoplehave becomeconcernedthatthe number of racehorses suffering catastrophic breakdowns while racing and training is increasing. Some veterinarians blame the widespread continued from page 1 are the additional breakdowns that MacLeod. "After transcription, the occurred during training. It has been RNAis transported to the cell's cyto use—somewouldevensay abuse—of argued that widespread corticoster plasm(outsidethenucleus)andtrans corticosteroids. oid use was an important causative lated into proteins. Bychanginggene Steroidsare a family ofmolecules that factor in many of these injuries. transcription.steroidsalterwhichpro- are chemically related to cholesterol. MacLeod, in collaboration with vet teins are made by the cells. For any Theyactby changingtherateat which erinary surgeon Susan Fubini, hopes given gene, transcription can be in certain genes are transcribed, or to better understand how steroids creased, decreased, or unaffected by coded, into RNA. This, in turn, alters changethe biologyofjointtissuesand steroid treatment." which proteins are produced by the learn howto minimize the drugs' del MacLeod is now working to uncover cells. Anabolic steroids, such as test eteriouseffects. Up to thispoint, there how the expression of the isolated osterone, are used by weight lifters have been few molecular studies on genesinfluencescartilagebiologyand andotherathletes to enhance muscle horsediseases, particularlythose that theonsetand progression ofjointdis growth and are the subject of great affect joint cartilage. eases such as arthritis. He hopes to concern in amateur and professional learn how the genes are expressed in sports. Corticosteroids, such as hy different areas of healthy cartilage, in drocortisoneanddexamethasone,are arthritic cartilage, andin bothnormal popular for their anti-inflammatory "Our objective is not to and inflamed joints that have been effects. generate data that treated with steroids. In addition, he Corticosteroidsarewidelyusedin race will continue isolating genes that are horses for a very good reason—they condemns steroid use, but involved in cartilage biology by clon arethemostpowerfulanti-inflamma rather to learn how ing four more equine-specific DNA tory agents available to veterinarians segments. andareextremelyeffectivein control steroids change jointtissue "Wewouldliketo distinguishbetween ling joint pain and lameness. Human cartilage changes caused by joint in athletessuchas baseballpitchers,ten physiology so that their flammation, or thediseaseprocess, as nis players, and long-distance run opposed to those induced by steroid ners also commonly use steroids to beneficial effects can be therapy. We also want to better un reduce pain and joint swelling. How optimized while their derstand howsteroids might actually ever, these medicationscarrytheseri protectcartilage from degradation by ous side effect of weakening cartilage deleterious effects are reducing the expression of protein- and ligaments in damaged joints and degrading enzymes that are released mayeven promotedegenerativejoint minimized." during inflammation." changes such as arthritis. Ultimately, MacLeod hopes to deter A highly publicized case in point was "Understanding the basic mecha minethenegativeandpositiveeffects the race horse Prairie Bayou, who last nisms of a disease process first and of steroids at the genetic level so that year won the Preakness and finished foremost offers the potential for pre the positive effects may somehow be second in the Kentucky Derby before vention," MacLeod explains. "By un optimized, perhaps through the de being euthenized after his left foreleg derstanding what changes occur as velopment of new steroids, and the shattered during the Belmont Stakes. disease develops, veterinarians may negative effects minimized or com Two Cornell veterinarians who per be able to target treatment to the ac pensated for. formed anautopsyontheyounggeld tual pathology and minimize the po ing concluded that steroids injected tentialofdamagingthejointcartilage." "Forthewell-beingof race horses, the into the horse's left fetlock joint had racing industry, and the people who graduallydegradeda criticalligament So far, MacLeod has isolated (or love the sport of racing, we need to cloned) several equine-specific gene until it finally broke. learnmoreabouthowcorticosteroids fragments that have allowed him to change the biology of joint tissues. Although the owners of Prairie Bayou use powerful new methods to study Our objective is not to generate data and many veterinarians aggressively equine joint disease. Specifically, he thatcondemnssteroid use, butrather disputedthisCornellconclusion, Uni has isolated piecesofhorse DNA from to learnhowsteroids changejointtis versityofMinnesotaresearchershave genesthatencodeimportantcartilage suephysiologyso thattheir beneficial reported that840 horsessufferedfatal proteins. effects can be optimized while their racingbreakdownsandanother3,566 "Onceisolated, theDNA segmentsare deleterious effects are minimized." • suffered nonfatal racing breakdowns usedtomeasuretherateatwhichthese intheU.S.in 1992alone. Notincluded genes are transcribed into RNA," says PROFILE Dr. Alan Nixon here," says Nixon. 'The College of Veterinary Medicine at Cornell, how ever, was the major draw. Iconsider this the most attractive school in the world for its rich academic, clinical, and research programs." His passion, Nixon admits, is hiswork. He can frequently be found in his research labs late at nightaftera busy day of surgery. His other interests include downhill skiing, hiking, sailing, windsurfing, and keeping tabs on the brood mare and two geldings he left in Colorado. At Cornell, Nixon spends about half his time inthe Large Animal Clinic, performing routine lamenessworkups and general joint and reconstructive surgeries such as knee and fetlock chip Equine orthopedic surgeonAlan Nixon's successful cartilage grafting techniques removals, removing flaps in horses with may have potential foruse in humans as well as in horses. OCD (osteochondritis dissecans, an abnormal cartilage growth), and his newly developed cartilage graft proce Almost weekly, Dr. Alan Nixon arthroscopic hip, elbow, shoulder, and dure. The rest of his time is spent boardsa planeforsome distant tendon surgeries in the horse. teachingorthopedics and conducting clinic to perform his highly specialized Nixon's career took root more than 30 research on cartilage grafts, tendon surgical techniques on horses. The years ago on his family's farm, which metabolism in horses, and innervation College of Veterinary Medicine profes covers more than 10,000 acres in in equine bones. sor is one of the few equine orthopedic southeastern Australia. Growing up, he His next frontier is molecular biology surgeons in the world who performs a and his two brothers worked cattle, research in cartilage defects and healing particular procedure that cures a horses, and sheep on the farm. While and studying how changes in genetic "wobbler," a horse with pinched nerves his brothers continuedfarming and run expression occurafter insult to a joint. in itsspinal cord. the family farm to this day, Nixon knew With vet school colleague Dr. James And he's the world's onlyequine as a young teen that he was interested MacLeod and researchers at the orthopedic surgeon using special in pursuinga career in veterinary University of Washington, Nixon is grafting methods he developed to science. He asked a local veterinarian if exploring growth factor geneticexpres resurface cartilage defects such as he could ride with him for several sion in damaged cartilage, such as fractures before arthritis sets in. The weeks to get a feel forwhat vets really osteoarthritic cartilage, to learn what technique, developed overthe past four do. He liked the feeling. can be done to improvedamaged years with Zweig funding, has been so At 17, Nixon went right from high joints. successful that its potential application school to veterinary college at the 'We hope to learn how to minimize to human joint repairs was published in University of Sydney in Australia. To damage and perhaps develop better the September, 1994 issueof iournal pursue more specialized training, he doses of external growth factor and of Orthopedic Research. continued on to Colorado State better timingof cartilage grafts to "Our main interests are the wear and University to do a residency in equine improvethe situation," he says. tear that occur in race and performance surgery and earned his masters in horsesand catching problems early 1983. After severalyears at the Will Nixon eventually returnto Australia? enough to preventarthritis. But if our University of Florida