Stress Chaperone GRP-78 Functions in Mineralized Matrix Formation

Mineralized matrix formation is a well-orchestrated event requiring several players. Glucose regulated protein-78 (GRP-78) is an endoplasmic reticulum chaperone protein that has been implicated in functional roles ranging from involvement in cancer biology to serving as a receptor for viruses. In the present study, we explored the role of GRP-78 in mineralized matrix formation. We observed changes in the expression of GRP-78 mRNA and protein upon in vitro differentiation of primary mouse calvarial cells. We also observed GRP-78 in the secretome of these cells suggesting an extracellular function during matrix formation. In-vitro nucleation experiments under physiological concentrations of calcium and phosphate ions indicate that GRP-78 can induce the formation of calcium phosphate polymorphs both by itself and when bound to type I collagen. We provide evidence that secreted GRP-78 can bind to DMP1 and Type I collagen independent of each other. Finally, we demonstrate that GRP-78 functions as a receptor for DMP1 endocytosis in pre-osteoblasts and primary calvarial cells. Our findings provide the proof of principle that that besides an intracellular function, GRP-78 plays a regulatory role during mineralized matrix formation.