The fundamental seal between periodontal connective tissue and the oral cavity is established by a specialized epithelium, the junctional epithelium (JE). The JE is shaped as a wedge positioned between periodontal stroma and tooth surface, consisting of cells stratified from a few to about 30 layers in the apical coronal direction. JE cells facing stroma and tooth tightly adhere to an external (EBM) and an internal (IBM) basement membrane, respectively. Ultrastructural images suggest that JE cell adhesion to both EBM and IBM is mediated by adhesion devices called hemidesmosomes, similar to those of epidermal keratinocytes. Hemidesmosome-mediated adhesion is likely to play a crucial role in the establishment and maintenance of those adhesive and differentiated properties that distinguish JE from the adjacent sulcular and gingival epithelia. Structural and functional knowledge of hemidesmosomes, however, is scarce, severely limiting our understanding of periodontal JE physiopathology. In periodontal disease, the JE is the primary site of destruction, followed by degeneration of dentogingival fibers. Following periodontal treatment, regeneration of the epithelium may occur, but generally at the expense of the dentogingival fibers, such that physiological structures anchoring the tooth are not reformed. Proper healing of periodontal lesions is therefore a main goal of dental research, and will require an ability to manipulate adhesive and differentiated properties of the JE. Our laboratory studies structure and function of a family of transmembrane heterodimers which regulate cell adhesion and differentiation, called the integrins. We recently found that the integrin alpha6beta4 is physically associated with hemidesmosomes, and may regulate their assembly. The integrin alpha6beta4 is expressed by JE cells at sites where they interface IBM and EBM. We therefore propose to: 1) characterize in detail the relationship between integrin alpha6beta4 and hemidesmosomal components in JE cells, by immunohistochemistry and immunoelectron microscopy on gingival tissues; 2) identify and characterize the IBM and EBM component that functions as a ligand for alpha6beta4, by a combination of protein chemistry and recombinant DNA methods; 3) define the role of alpha6beta4, its ligand and other matrix components in JE, by studying how the presence and the expression of these molecules affects adhesive and differentiated properties of cultured JE cells. We are confident that this information will significantly advance our understanding of JE physiopathology, and may consequently clarify several aspects of onset, progression and healing of periodontal disease.
