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, 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 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 . 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 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 College of Veteri "Maybe to retire," he says. 'There's so techniquesand knowledge can be nary Medicine in Gainesville, he came much going on here in this country it's adapted to humans,so much the to Cornell. phenomenal. I believe it's unsurpassed anywhere in the world—and I love it." • better," he says. "I chose orthopedics because Iconsider Nixon is accustomed to being a pioneer this field the most challenging and in equine orthopedics. He and his exciting, and Icame to NewYork for colleagues were also the first to develop the quality of the horses and racing Zweig-funded Research Helps Extend a Racing Career

A large part of orthopedic surgeon Alan Nixon's day is spent in the operatingroom.Onerecentdayfound Three incisions in the horse's knee allow the insertion of an him performing a procedure to cor arthroscope, surgicalinstruments, and a double syringecontaining rect damage to the carpus, or knee the cartilage cell matrix. joint, of a three-year old racehorse. After inserting a screw to repair the injury, he injected a matrix contain ing cartilage cells andgrowthfactor to helpthecartilageregenerate.Thetech nique, which Nixon developed with Zweig support, will help prevent ar thritis from forming in the joint. The operation was successful and Nixon predicted the fillywould soon return to the trackto finish her racingcareer.

Nixon checks the television monitorto assess the distribution of the cartilage cell matrix.

Photographs byDavid Lynch-Benjamin X-rays taken during the procedure show the screw Nixon has inserted into the knee as well as the arthroscope and surgical tools.

Moving the sedated horse from a gurney to the padded floor of the recovery room takes the coordi nated efforts of nine people.

Waiting for the anesthesia to wear off, veterinary student Charles Brockettand anesthesiology techni cian Joan Ballenstedt monitor the horse in the recovery room. In a few hours, she'll be up and around. New Urine Test Helps Detect Bone Weakness

To learn the specific techniques modified from the methods devel needed, suchas amino acidsequenc oped for humans, the veterinary sci ing and collagen cross-link analysis, entists are currently developing Minor spent a month in Washington baselines ofnormal values for horses with Dr. Erye and enlisted him as a at different ages. Theyhavefound, for consultantfortheequineproject.With example, thatthevalues for the bone- fellow veterinary scientists Drs. specific "cross-linked" (covalently FernandodeNoronha, LennartKrook, linked) amino acids in the foal are andSusanFubini, Minorhassuccess three to five times higher than in the fullydeveloped a biochemical test for mature horse. This difference might equineurinethatprovidestheneeded be expected, since the foal is growing informationonbonegrowthanddeg bone much more rapidly and there radation. To doso, theytestedthe two fore experiences much more bone commercially available human tests turnover. with horses. One of the kits strongly Next year, after the researchers have reacted with the horse urine and al completedthenormalrangeofvalues lowed the researchers to isolate cer- for horses of different ages, they will test athletic horses of two and three years of age and compare the values with those of younger and older "Our hope is to be able to horses. They plan to test horses that Ronald R. Minor, D.V.M., Ph.D. inexpensively identify show no indication of bone break Breakdown injuries of the bone, down and use the values obtained as such as "bucked shins," saucer athletic horses at risk for baselines. They will then compare fractures of the cannon bone, and thosevalueswithvalues derived from othertypes offractures commonlycut many traumatic and life- horses that have experienced bone shortthecareersofracehorses.Weak threatening injuries." fractures during racing. ened bone may contribute to these "Our hope is to be able to inexpen musculoskeletal injuries. While the sively identify athletic horses at risk normal process of bone growth in tain linked amino acids, the building formanytraumaticandlife-threaten- volves some bone degradation and blocks of the protein. Unlike most ing injuries," says Minor. "As the replacement, called "bone turnover," amino acids, the isolated amino acids methodof quantifyingboneturnover bone becomes weaker when there is are not reutilized in bone production becomesmoresophisticated,we hope more degradation than productionof butare excreted in the urine. Theyare to be able to analyze the urine of colts bonematrix.Yet,currentequinesports specific to collagen, the majorprotein and fillies receiving different diets medicine lacks a simple way to mea (suchas excessiveorincorrectdietary ofbone. sure such bone breakdown. supplements), experiencingdifferent "Collagenis the glue that holds every Recently, however, a quick and inex growth rates, and beinggiven various thing in the body together," explains urine test for humans that drug therapies (such as corticoster Minor, who has spent more than 20 oids and anabolic steroids). Then we measures bone turnover was devel years studyingcollagenin severalspe oped by Dr. David Erye at the Univer might be able to determine if any of cies, including an 11,000 year-old sity of Washington School of Medi these factors are changing the col mammothwhoseboneswerediscov cine. The test can determine if the lagen degradation values in urine. ered in Utah in 1988. "Collagen, in Such a test would also allow us to delicatebalancebetweennormalbone fact, makes up morethanone-thirdof growth and degradation has become identifyabnormalitiesin bonegrowth thetotalproteinin all speciesandcon disrupted. Usingfundsfrom theHarry in the young horse. With a better un stitutes the major framework that is M. Zweig Memorial Fund, Ronald R. derstandingof the signs of boneturn mineralized to form bone. Whenever Minor, Ph.D., V.M.D., an experimen over, horse owners and trainers, in bone is degraded, collagen molecules tal pathologist at Cornell's College of consultationwithveterinarians,could are broken up into free amino acids Veterinary Medicine, and his col then make informed decisions con thatareeitherreutilizedorexcretedin leagues are adapting the procedure cerning the effects of diet, training, the urine." for equineurine to identifyand quan andracingmanagementbasedonthe tify bone resorption in horses. Using the test, a chemical assay they effects of their regimens." • COMMITTEE MEMBER PROFILE William H. Welch

William H. Welch, 54, a Zweig 'The thoroughbred business is going Committee member and through a shake up with new tax laws executive administrator of the New York that are no longer as favorable to horse Thoroughbred Breeding and Develop breeders," said Welch during an August ment Fund, "practically grew up on a interview while he was at Saratoga for horse" in the Genesee Valley. Hewas the races. 'We'retrying to change with steeplechase racing and fox hunting by the times and find ways to encourage age 9, and later went to Cornell people to continue breeding." University thinking he'd become a This past year has been one of the veterinarian. He got sidetracked, fund's most successful. New York bred however, and graduated in 1962 with a horses broke theirrecord for winning major in economics. graded or group races, the most Unsure of what he wanted to do, prestigious races inthe industry. Welch became a deputy sheriff in Seventeen New York breds won 19 Livingston County for several years and such races, two more than the previous during that time, decided to make record set in 1992. Some $900,000 of horses the focus of his career. After the $40 million in purses in 1993 was attending the Jockey Club School for won bythoroughbreds bred in New racing officials, he worked for several William H. Welch York, once again placing the state years as a part-time sheriff and part- among the nation's leaders. Si 2 million a year—for incentive and time placing and patrol judge at "In addition to the $12 million we put development programs for NewYork Aqueduct and the then newly-opened back into the economy, more than bred horses. The fund supports races Finger Lakes Race Track in $200 million has been spent renovat Canandaigua. for New York breds and bestows ingformer dairy farms into vital horse almost 1,500 awards to breeders, In 1967, Welch moved to New York farms," Welch says. "All told, the stallion owners, and ownersof winning City to take the position of assistant breedingindustry contributes $2 billion horses as well as purse enrichments to director of the New York Breeders to the overall economy of NewYork. Bureau. Named director in 1971, he New York bred restricted races. In For fear of boasting, I believe our fund addition, the fund gives two percent of was one of the driving forces inthe has been one of the most successful its resources to the Harry M. Zweig passage of the breeding and develop programs in the state in terms of Memorial Fund for Equine Research at ment law, which, after two vetoes, the lighting a sparkin agriculture and the the New York State College of Veteri governor finally signed into law in economy while also promoting 1973. The law changed the name of nary Medicine at Cornell. research through the Zweig Fund." the Breeders Bureau to the New York Welch, a bachelor, isan avid deep sea StateThoroughbred Breeding and fisherman, going aftertuna, shark, and Development Fund Corporation and "I believe our fund has marlin in particular. But his love of mandated that the corporation would riding has never left him, and he still receive one-halfof one percent of the been one of the most likes to climb on a horse when he can. on and off track handle—approximately successful programs in the state in terms of lighting a spark in agriculture and the economy while also promoting research through the Zweig Fund." TheHarry M. Zweig Memorial FundforEquine Research honorsthelateDr. Harry M. Zweig, adistinguished veterinarian, andhisnumerouscontribu tionsto the state's equine industry.In 1979, byamendment to the pari-mutuel revenue laws, the New York State legislature created the Harry M. Zweig Memorial Fund to promote equine research at the College of Veterinary Medicine,CornellUniversity. TheHarryM.ZweigCommittee isestablished for the purpose of administering the fund and is composed of individuals in specified state agenciesand equine industrypositionsand others who repre sent equine breeders, owners, trainers, and veterinarians.

The Harry M. Zweig Memorial Fund Committee

Daniel J. Burke Patricia Wehle LongfordFarms Wehle Stock Farm Richard Corbisiero, Ir. William H. Welch Chairman, NYS Racingand Wagering Board ExecutiveAdministrator NYS Thoroughbred Breeding and Development Fund Bruce Hamilton Executive Secretary William B. Wilmot, DVM Harness Horse BreedersofNYS Saratoga Springs, New York John L. Hardy Theodore J. Zornow Tuckerand Hardy Associates Avon Farms John E. Jagar, DVM Anna Zweig Millbrook, New York Widow ofDr. Zweig

Charles Knauss, Jr. Robert D. Phemister, DVM, PhD (Chairman) Executive Director Dean, College ofVeterinary Medicine at Cornell Agriculture and NYS Horse Breeding University Development Fund Harry D. Snyder Chairman, NYSRacing Commission

Zweig News Capsule College of Veterinary Medicine Cornell University C-105 Schurman Hall Ithaca, NY 14853-6401

Permission is granted to reproduce material appearing in this publication, provided that full acknowledgment is made of the source and no change is made without approval, by notifyingthe editor at 1150 Comstock Hall, Cornell University, Ithaca, NY 14853-0901. The Zweig News Capsule is produced periodically throughout the year to report on research at the College of VeterinaryMedicine, Cornell University, funded by the Harry M. Zweig Memorial Fund for Equine Research. Writer: Susan S. Lang Editor: Mike Powers Designer: Lorraine Heasley Photographer: David Lyncn-Benjamin

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