Agrin expressed by osteocytes: effects on osteocyte differentiation, bone formation during skeletal development and osseointegration of titanium implant with nanotopography

Abstract

Osteocytes are the most abundant cells in bone tissue with key role for the skeleton function. They are derived from the osteoprogenitor lineage, exhibit a dendritic morphology and are embedded by the mineralized matrix during the bone formation process. Osteocytes regulate the activity of osteoblasts and osteoclasts through the secretion of factors that modulate several signaling pathways, which contribute to bone homeostasis and also to the osseointegration of titanium (Ti) implants. Thus, the study of molecules that can favor these processes are essential in bone biology. Our research group showed the participation of the extracellular matrix protein Agrin in osteoblastic differentiation and the osteoinductive potential of Ti with nanotopography. However, the expression of Agrin in osteocytes, as well as its participation in both bone formation and the osseointegration of Ti implant with nanotopography have not yet been addressed. Therefore, the aim of this study is to investigate the expression of Agrin by osteocytes and its effects on the differentiation of these cells, bone formation during skeletal development and osseointegration of Ti implants with nanotopography. To reach this goal, we will evaluate: 1) the participation of Agrin in the differentiation of osteocytes using the osteocytic lineage Ocy454 and the involvement of the BMP, Wnt, Notch and Hippo-Yap / Taz signaling pathways; 2) the participation of Agrin expressed by osteocytes in bone formation during skeletal development using genetically modified transgenic mice with conditional deletion of Agrin expression in osteocytes; 3) the participation of Agrin in the interaction between osteocytic lineage Ocy454 and Ti with nanotopography, compared to control Ti, and the involvement of the BMP, Wnt, Notch and Hippo-Yap / Taz signaling pathways; and 4) the participation of Agrin expressed by osteocytes in the osseointegration of Ti implant with nanotopography, compared to control Ti implant, using implants installed in the oral cavity of genetically modified transgenic mice with conditional deletion of Agrin expression in osteocytes. As the role of Agrin in the osteocyte activity and the mechanisms involved are still unknown, the results generated by this project will be scientifically and therapeutically important, as Agrin can be a target protein for the development of new therapeutic strategies that involve bone remodeling mediated by osteocytes and that favor events related to the process of osseointegration. (AU)