Endoplasmic Reticulum Chaperone GRP78 Interacts with DMP1 and Functions in Biomineralization

Glucose regulated protein-78 (GRP78) is a dynamic endoplasmic reticulum chaperone of the heat shock family that is involved in the unfolded protein and cellular stress response. GRP78 and other GRPs are known to bind Ca2+ in the ER to modulate the levels of calcium in the cell and respond to ER stress. We have demonstrated earlier that GRP78 is expressed by osteoblasts and odontoblasts and localized in the mineralized matrices of bone and dentin. Interestingly, GRP78 functions as a receptor for dentin matrix protein 1 (DMP1), a key protein involved in matrix mineralization. In this project, we explore the synergistic function of GRP78 and DMP1 during mineralization. Previous studies demonstrate that upon stress, GRP78 can translocate from the ER to the cell surface. Additionally, our lab showed that GRP78 is a receptor for DMP1. We demonstrate how GRP78 interacts with DMP1 to promote osteogenic differentiation and matrix mineralization in periodontal ligament stem cells; moreover, we determine the mechanism of GRP78-DMP1 complex internalization and subsequent translocation intracellularly to aid in cell differentiation through in vitro cell culture work. Through an in vivo mouse model, we determine the functional significance of GRP78 in mineralization with periodontal ligament stem cells. Overall, our overarching goal is to determine GRP78’s functional significance in mineralization to ultimately provide a novel way to achieve bone regeneration in the periodontium.