Mechanisms of inhibition of BMP-induced bone formation by gingival connective tissues.
Lead Research Organisation:
Queen Mary University of London
Department Name: UNLISTED
Abstract
New bone formation is an important requirement during the treatment of gum disease and treatments with dental implants. The evidence suggests that the gum tissues above the bone may prevent adequate new bone formation, even when stimulate by specific bone inducing proteins (BMPs). There are various possible mechanisms that may inhibit the action of these proteins, but little is know about their activity within the gums Thus this research will test the different pathways of inhibition in order to determine the reasons why adequate bone is so difficult to stimulate during these types of complex dental treatment. We plan firstly to measure the production of specific inhibitors to BMPs in the gums, secondly to investigate the ways that cells in the gums respond to stimulation by these proteins, and to determine if the normal signals involved in making bone form are blocked in these tissues.
Technical Summary
Empirical evidence suggests that superficial connective tissues are able to prevent normal osteogenesis, and bone formation induced by pharmacological application of bone morphogenetic proteins (BMPs). The aim of this project is to investigate the mechanisms of this observed inhibition. Specifically the objectives of the studies are :
1) to investigate the expression of BMP inhibitors noggin, chordin, follistatin, sclerostin and ectodin in gingival connective tissue and cultured gingival fibroblasts both constitutively and following BMP stimulation, by cell culture, real time RT-PCR and in situ-hybridisation
2) to investigate the expression of BMP receptors in gingival and other connective tissues by immunohistochemistry and in situ hybridisation;
3) to investigate the role of Smad - dependent signalling pathways in the regulation of expression of BMP-inhibitors by examination of SMAD expression, effects of dominant negative SMAD expression, and expression of inhibitory SMADs.
4) to investigate the role of p38 Map Kinase pathways in the regulation of expression of BMP-inhibitors using specific inhibitors.
5) to carry out definitive intervention experiments to determine the principle mechanisms of bone inhibition by superficial connective tissues using gene silencing or transfection techniques to modulate the principle inhibitory pathways found in earlier experiments.
The project provides excellent training opportunities to develop research skills in aspects of regenerative medicine, molecular biological techniques and bone biology. Additionally it is hoped that study of these questions will provide new insights into clinical aspects of bone regeneration, particularly in dental implantology and periodontology, and ultimately improve clinical procedures in these areas.
1) to investigate the expression of BMP inhibitors noggin, chordin, follistatin, sclerostin and ectodin in gingival connective tissue and cultured gingival fibroblasts both constitutively and following BMP stimulation, by cell culture, real time RT-PCR and in situ-hybridisation
2) to investigate the expression of BMP receptors in gingival and other connective tissues by immunohistochemistry and in situ hybridisation;
3) to investigate the role of Smad - dependent signalling pathways in the regulation of expression of BMP-inhibitors by examination of SMAD expression, effects of dominant negative SMAD expression, and expression of inhibitory SMADs.
4) to investigate the role of p38 Map Kinase pathways in the regulation of expression of BMP-inhibitors using specific inhibitors.
5) to carry out definitive intervention experiments to determine the principle mechanisms of bone inhibition by superficial connective tissues using gene silencing or transfection techniques to modulate the principle inhibitory pathways found in earlier experiments.
The project provides excellent training opportunities to develop research skills in aspects of regenerative medicine, molecular biological techniques and bone biology. Additionally it is hoped that study of these questions will provide new insights into clinical aspects of bone regeneration, particularly in dental implantology and periodontology, and ultimately improve clinical procedures in these areas.