Apoptosis Regulated by Fibronectin and Its Receptors

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The goal of these studies is to understand the mechanism by which proteolytic fragments of fibronectin (FN) mediate apoptosis in periodontal ligament (PDL) cells. Although the etiology of periodontal disease has been attributed to bacterial pathogens, several components in the pathogenesis of this disease remain poorly understood. One such area is the role of matrix fragments generated by bacterial proteinases and by inflammatory host-derive enzymes in the progression of periodontal disease. Proteases expressed by several putative periodontal pathogens readily cleave FN into multiple fragments, which are found in vivo and in association with periodontally disease sites. One such fragment is a 40 kDa chymotryptic fragment which contains the heparin-binding domain and part of the alternatively spliced V region of FN and can be generated by the chymotrypsin-like enzyme produced b Prevotella intermedia. Both this 40 kDa fragment and a longer recombinant (V+H-) fragment that also has the heparin-binding domain and the alternatively spliced V region of FN induce apoptosis in PDL cells. In addition, fragments of FN alter cell motility and enhance proteinase expression in PDL cells. These findings lead to the hypothesis that proteolytic fragments of FN generated by bacterial and/or host inflammatory cell proteinases affect several PDL cell functions including, survival, thereby exacerbating the degradation of periodontal tissues and contributing to disease progression. The specific aims are to: (1) Characterize the matrix parameters by which the 40 kDa FN fragment induces apoptosis in PDL cells; (2) Identify the cell surface receptors for the 40 kDa FN fragment, and for the 40 kDa-containing recombinant FN fragments that are involved in regulating apoptosis in PDL cells; and (3) characterize the signaling pathways by which the 40 kDa FN fragment and other fragments containing the 40 kDa region regulate apoptosis of PDL cells. These findings will contribute to our understanding of the pathogenesis of periodontal disease and to our basic understanding of the regulation of apoptosis by the extracellular matrix.