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

Insights into Etiology and Innovative TreatmentModalities for Osteoporosis, Fracture Healing,Osteolysis and OsteonecrosisOsteocytes, osteoclasts, osteoblasts andpluripotent cells within bone marrowform a functional syncytium linking cellsdeep within bone tissue to cells on bone surfacesand/or within close proximity to the vascularsystem. This cellular network permits transmissionof chemical, electrical and mechanical signalsbetween cells that have the machinery to remodelbone tissue (osteocytes, osteoclasts,osteoblasts) and those withthe capacity to affect the populationof bone remodeling cells(pluripotent cells and monocytes inthe marrow, circulating blood) aswell as to invoke a systemicresponse. Remodeling eventsappear highly “choreographed,”but the signaling and timing ofinteractions between osteocytes,osteoclasts and osteoblasts are notclear. A primary focus of theMusculoskeletal MechanobiologyGroup is to understand theseinteractions. Specifically, we aimto uncover mechanisms underlyingprocesses of growth, adaptation, and repair ofmusculoskeletal tissues, in particular, bone.Interstitial fluid flow is a likely mechanismfor mechanochemical transduction in bone. Wehave developed innovative methods to studymechanical load-induced fluid flow and masstransport through tissue, using fluorescent tracersof different molecular weights. Applying thesemethods ex vivo in sheep, in vivo in rat, and in vitrousing bone explants, we have proven thatmechanical loading drives fluid flow throughbone. We have also shown that fluid displacementsresulting from mechanical loading enhancemolecular transport from the blood supply to theosteocytes, thus playing an important role inosteocyte viability. This finding has importantclinical implications for healing bones. We haveThe Department of Biomedical EngineeringMelissa L. Knothe Tate, Ph.D.also developed theoretical computer models topredict flow patterns under simulated conditions.By comparing these predictions with actualexperimental results, we have begun to explicatethe relationship between mechanical loadingparameters and fluid dynamics in bone. To betterunderstand molecular transport processes throughthe relatively impermeable tissue of bone, wehave devoted a major effort tostudying the spaces through whichextravascular fluid flows. We areexploiting insights gained fromthese studies to develop drugdeliverysystems for skeletaltissues and for new bioactiveendoprostheses designed tooptimize osseointegration. Inaddition, we are applying thisknowledge to optimize functionof tissue-engineered bone.Furthermore, new prophylactictreatment modalities to preventosteopenia due to osteoporosisand disuse are under study.In sum, we are achieving aglobal picture of fluid flow and mass transport inbone that has tremendous implications for cellviability and integrity, as well as the governanceof functional adaptation and repair within bonetissue. Furthermore, we can link spatial information(e.g., local architecture) to distribution offlow and to osteocyte signaling. We are correlatingthis information with the distribution ofcytokines through the tissue, thereby establishinga biophysical basis for mechanotransduction andthe biology underlying processes associated withadaptation and repair. These concepts haveprovided the foundation for a new theory ofbone (re)modeling that enhances our understandingof the clinical implications of fluid flow andmass transport for bone in health and disease.Knapp, H.F., Reilly, G.C., Stemmer, A., Niederer, P., and M.L. Knothe Tate (2002) Development of preparationmethods for and insights obtained from Atomic Force Microscopy of fluid spaces in corticalbone. Scanning 24:25-33.Knothe Tate, M.L., Tami, A.E.G., Bauer, T.W., and U. Knothe (2002) Micropathoanatomy of osteoporosis- indications for a cellular basis of bone disease. Adv. Osteoporotic Fracture Manage. 2:9-14.Tami, A.E., Nasser, P., Verborgt, O., Schaffler, M.B., and M.L. Knothe Tate (2002) The role of interstitialfluid flow in the remodeling response to fatigue loading: a theoretical and experimental study. J. BoneMiner. Res. 17:2030-2037.Steck, R., Niederer, P., and M.L. Knothe Tate (2003) A finite element analysis for the prediction ofload-induced fluid flow and mechanochemical transduction in bone. J. Theoretical Biol. 220:249-259.Steck, R., Gatzka, C., Schneider, E., Niederer, P., and M.L. Knothe Tate (2003) Measurement of bonesurface strains on the sheep metacarpus in vivo and ex vivo. Veterinary Comparative Orthop. Traumatol.16:1-9.ORTHOPAEDICBIOLOGY ANDBIOENGINEERINGTHE KNOTHE TATELABORATORYPOSTDOCTORAL FELLOWSSanjay Mishra, Ph.D.Roland Steck, Ph.D.RESEARCH FELLOWPavel Netrebko, M.D.GRADUATE STUDENTSJosée Adamson, M.S.Andrea Tami, Dipl. Masch.-Ing.UNDERGRADUATE STUDENTSMegan Dines 1Scott Koncal 1Ravi Patel 2Jaime Streem 3Christine Tiberio 11Cornell University, Ithaca, NY2Case Western Reserve Univ.,Cleveland, OH3Univ. of California at LosAngelesHIGH SCHOOL STUDENTSMegan ColeyTeleschia LawMarissa SchafferCOLLABORATORSJ. Iwan Alexander, Ph.D. 1Harihara Baskaran, Ph.D. 2Thomas W. Bauer, M.D., Ph.D. 3,4Dwight Davy, Ph.D. 1Steven Eppell, Ph.D. 5Miklos Gratzl, Ph.D. 2Ulrich Hopfer, M.D., Ph.D. 6Joseph Iannotti, M.D., Ph.D. 3Ulf Knothe, M.D., Dr. Med. 3Ronald J. Midura, Ph.D. 7DeVon Griffin, Ph.D. 81Dept. of Mech. and AerospaceEngineering, Case WesternReserve University, Cleveland,OH2Dept. of Chem. Eng., CWRU3Dept. of Orthopaedic Surgery, CCF4Dept. of Anatomic Pathology, CCF5Dept. of Biomed. Eng., CWRU6Dept. of Electrophysiology,CWRU7Dept. of Biomed. Eng., CCF8NASA Glenn Research Center,Cleveland, OHMelissa L. Knothe Tate, Ph.D.37