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

Cellular and Molecular Mechanisms ofWound Healing in Orthopaedic SoftTissue and OsteoarthritisOur primary interest is the cellularand molecular processes in thehealing of wounds in the joint tissues.While a substantive literature documents theimportance of the knee joint meniscus, relativelylittle is known about the cell biology of thistissue. The meniscus is especially interesting inthe context of wound healing as it can repairwounds, whereas articular cartilage, a verysimilar tissue, does not.The Cell and Matrix Biology of theNormal MeniscusAt least three distinct populations of cellscan be recognized in the meniscus. Most of theinner nonvascularized portion is populated bycells that are round or oval with a pericellularmatrix of type VI collagen. We have termedthese cells “fibrochondrocytes.” The outermeniscus has fibroblast-like cells with longcytoplasmic processes that interconnect withsimilar cells through gap junctions. Elongatedcells that lack cytoplasmic extensions populatethe superficial zones of the meniscus. Our in vivoand in vitro studies suggest that these cells initiatethe wound-healing process in the meniscus.The meniscus is a fibrocartilage with anextracellular matrix composed mainly of type Icollagen, the typical collagen of fibrous tissues,and small amounts of type II collagen, thegenetic type of collagen found in hyalinearticular cartilage. We have established thatthese two collagens are found together in ahighly organized fibrillar meshwork.The Department of Biomedical EngineeringRepair Mechanisms in the MeniscusWe have developed in vivo and in vitromodels for studying the response of meniscal cellsto wounds in the tissue. The fibrochondrocytesand fibroblast-like cells of the normal meniscusare in a quiescent state with minimal expression ofthe fibrillar collagen genes. With wounding,however, the mRNA levels for type I and type VIcollagen and other matrix proteins are dramaticallyincreased, as assessed by RNase protection assay.The cells in the superficial region undergo divisionand express an alpha smooth muscle isoform. Thecrevice of the wound becomes populated by cellsthat appear to come from the superficial zone.Interestingly, the cells of the meniscus can migrateinto acellular areas created by apoptosis ofresident cells, a phenomenon that apparently doesnot occur in articular cartilage. With time, anintegration of tissues on either side of the woundoccurs.Tissue Engineering of MeniscusOur studies show that the meniscus has itsown distinctive healing process. We are exploringthe use of different macromolecules that, wheninserted into wounds, should promote the healingprocess.Type VI Collagen in the PericellularMatrices of Connective Tissue CellsThe physical and chemical stimuli to a cellmust traverse any pericellular coating it has. Somecells, like chondrocytes and fibrochondrocytes, aresurrounded by a distinct pericellular matrix oftype VI collagen. We can study the structural andfunctional aspects of this pericellular matrix andhow it controls signaling from the matrix to thecell.Kambic, H.E., Futani, H., and C.A. McDevitt (2000) Cell, matrix changes and alpha-smooth muscle actinexpression in repair of the canine meniscus. Wound Repair Regen. 8:554-561.Arnoczky, S.P., and C.A. McDevitt (2000) The meniscus: structure, repair, and replacement. In: Buckwalter,J.A., Einhorn, T.A., and S.R. Simon SR, eds. Orthopaedic Basic Science. 2nd ed. Park Ridge,IL: American Academy of Orthopaedic Surgeons, pp. 531-545.Wildey, G.M., Billetz, A.C., Matyas, J.R., Adams, M.E., and C.A. McDevitt (2001) Absolute concentrationsof mRNA for type I and type VI collagen in the canine meniscus in normal and ACL-deficientknee joints obtained by RNase protection assay. J. Orthop. Res. 19:650-658.McDevitt, C.A., Mukherjee, S., Kambic, H., and R. Parker (2002) Emerging concepts of the cell biologyof the meniscus. Curr. Opin. Orthop. 13:345-350.Kambic, H., and C. McDevitt (2002) Distribution and spatial relationship of collagen type I and type IIin the canine meniscus. Poster 0902, 48th Annual Meeting of the Orthopaedic Research Society, February10-13, 2001, Dallas, TX.Mukherjee, S., and C.A. McDevitt (2003) The superficial zone cells initiate a wound healing process incanine meniscus in vitro [poster]. Trans. Orthop. Res. Soc. vol. 28.Kim, J.H., Billetz, A., Iannotti, J., and C.A. McDevitt (2003) Isolation of a new cell-pericellular matrixstructure from the biceps tendon: longitudinal chains of type VI collagen surround linear arrays of cells[poster]. Trans. Orthop. Res. Soc. vol. 28.ORTHOPAEDICBIOLOGY ANDBIOENGINEERINGTHE MCDEVITTLABORATORYPOSTDOCTORAL FELLOWSSarmistha Mukherjee, Ph.D.Cassius Iyad Ochoa Chaar, M.D.Manojkumar Valiyaveetil, Ph.D.Manojkumar Valiiyaveettil, Ph.D.GRADUATE STUDENTCarlumandarlo Zaramo, B.S.TECHNOLOGISTKristin Rundo, B.S.Cahir A. McDevitt, Ph.D.COLLABORATORSJack Andrish, M.D. 1Brian L. Davis, Ph.D. 2David R. Eyre, Ph.D. 3Joseph P. Iannotti, M.D., Ph.D. 1John R. Matyas, Ph.D. 4Ronald J. Midura, Ph.D. 2John S. Mort, Ph.D. 5Richard D. Parker, M.D. 1Kimerly A. Powell, Ph.D. 2John Sandy, Ph.D. 61Dept. of Orthopaedic Surgery,CCF2Dept. of BiomedicalEngineering, CCF3Dept. of Orthopedics, Univ. ofWashington, Seattle4Dept. of Anatomy andPathology, McCaig Ctr. forJoint Injury and Arthritis Res.,Univ. of Calgary, Alb.,Canada5Shriners Hospital, Montreal,PQ, Canada6Shriners Hospital, Tampa, FLCahir A. McDevitt, Ph.D.39