Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of Biomedical EngineeringRegulation of Growth Plate Chondrocytesby Nuclear Hormone ReceptorsORTHOPAEDICBIOLOGY ANDBIOENGINEERINGChildhood obesity, a rapidly growingconcern, now threatens one in fourchildren with long-term health problems.Recent advances in the understanding ofadipogenesis and lipid metabolism at themolecular level have revealed the existence of afamily of nuclear hormone receptors that linknutritional signals to the control of geneexpression, and are induced or activated inresponse to a high-fat diet. These molecules,termed peroxisome proliferator-activatedreceptors (PPARs), are also expressed in boneand cartilage and interfere with thyroid hormonereceptor (TR)-mediated gene transcription incells in which PPARs and TRs are co-expressed.Given that peroxisomal function isrequired for normal endochondral ossificationand that thyroid hormone plays a central role inregulating skeletal maturation at growth plate, itis reasonable to ask if crossstalk exists betweenTR- and PPARmediatedtranscriptionalregulation in growthplate chondrocytes.Crosstalk between theTR and PPAR signalingpathways in growthplate cells may havedirect clinical implicationsregarding theetiology of an obesityrelatedhip disease inchildren, slipped capitalfemoral epiphysis. Inour laboratory, we aretesting the hypothesisthat PPARs areinducible repressors ofTR-mediated genetranscription in growthplate chondrocytes. Thespecific aims of thiswork are: (1) todocument the expressionof PPAR isoforms in the growth plate and toestablish if PPARs are co-expressed with TRs inindividual growth plate chondrocytes; (2) todetermine if exposure of growth platechondrocytes to PPAR activators results ininduction of PPAR expression and activation ofPPAR-mediated gene transcription in these cells;(3) to characterize the molecular interactions ofPPARs with TRs and retinoid X receptors ingrowth plate chondrocytes and describe theeffect of these interactions on TR-mediated genetranscription; and (4) to define the effects ofPPAR activation on thyroid hormone-inducedgrowth arrest and terminal differentiation ofgrowth plate cells.We are also pursuing translational researchopportunities focused on the growth plate. Wehave recently developed a rat model of physealbar formation and are using this model to developnovel strategies for regeneration of physealcartilage to prevent growth abnormalitiesfollowing physeal injury. Another area of stronginterest is the investigation of the molecularmechanisms involved in the Heuter-Volkmanphenomenon, in which growth plate cartilageslows down its growth in response to compressiveforces and speeds up its growth in response totensile loading. We are developing an instrumentedsurgical staple that will be inserted acrossthe rat proximal tibial physis to provide real-timemeasurements of the progressive compressiveforces generated by the physis growing against thestaple.These projects provide several opportunitiesfor training of residents, fellows, doctoral, orpostdoctoralstudents at manylevels of scientificinquiry. From basicmolecular andcellular biologytechniques to animalsurgery and tissueengineering, traineeswill emerge fromtheir experience inour laboratory witha strong backgroundin performing basicscience andtranslational researchprojects and willgain an appreciationfor what is requiredto be a successfulclinician-scientist.R. Tracy Ballock, M.D.THE BALLOCKLABORATORYINVESTIGATORYvonne Shao, Ph.D.COLLABORATORSRobert E. Guldberg, Ph.D. 1Brian Johnstone, Ph.D. 2Jean F. Welter, M.D., Ph.D. 2Matthew C. Stewart, D.V.M., Ph.D. 21Dept. of Mechanical Engineering,Georgia Inst. of Technol.,Atlanta, GA2Dept. of Orthopaedics, CaseWestern Reserve Univ.,Cleveland, OH1Dept. of Mechanical Engineering, Georgia Inst.of Technol., Atlanta, GA2CDept. of Orthopaedics, Case Western ReserveUniv., Cleveland, OHBallock, R., Mita, B.C., Zhou, X., Chen, D.H., and L.M. Mink (1999) Expression ofthyroid hormone receptor isoforms in rat growth plate cartilage in vivo. J. BoneMiner. Res. 14:1550-1556.Ballock, R.T., Zhou, X., Mink, L.M., Chen, D.H., Mita, B.C., and M.C. Stewart (2000)Expression of cyclin-dependent kinase inhibitors in epiphyseal chondrocytes inducedto terminally differentiate with thyroid hormone. Endocrinology 141:4552-4557.Ballock, R.T., Zhou, X., Mink, L.M., Chen, D.H., and B.C. Mita (2001) Both retinoicacid and 1,25(OH)2 vitamin D3 inhibit thyroid hormone-induced terminal differentiationof growth plate chondrocytes. J. Orthop. Res. 19:43-49.Marcelino, J., Sciortino, C.M., Romero, M.F., Ulatowski, L.M., Ballock, R.T., Economides,A.N., Eimon, P.M., Harland, R.M., and M.L. Warman (2001) Human disease-causingNOG missense mutations: effects on noggin secretion, dimerformation, and bone morphogenetic protein binding. Proc. Natl. Acad. Sci. U.S.A.98:11353-11358.35