Role of DMP1-mediated GRP78 activation in osteoimmunomodulation of periodontal ligament stem cells

Abstract

The oral microbiome dysbiosis that causes periodontal disease leads to disruption of various signaling pathways that can result in alveolar bone degradation and subsequent tooth loss. Previous studies have demonstrated the potential of stem cell-based therapies in regeneration of the lost periodontium for the preservation of natural dentition. Periodontal ligament stem cells (PDLSCs) have osteoblast differentiation potential and their proximity to bone makes them an ideal candidate for regenerative therapies. Dentin matrix protein 1 (DMP1), a non-collagenous extracellular matrix protein, is integral to mineralized tissue formation due to its dual roles as an extracellular mediator of hydroxyapatite deposition and intracellular regulator of osteoblastogenesis. Heat shock protein 5A (GRP78) is a master regulator of the endoplasmic reticulum stress response and previous studies in our laboratory have also demonstrated its function as a membrane receptor for DMP1. Bulk RNA sequencing analysis of PDLSCs and PDLSCs overexpressing GRP78 (PDLSCs GRP78) with or without treatment with DMP1 was conducted to evaluate alterations to the differentially expressed gene profiles. This study aims to elucidate pathways in PDLSCs that are altered upon treatment with DMP1 to further characterize its relationship with GRP78 and cell stress signaling cascades. Pathway enrichment analysis of each transcriptomic profile demonstrated enrichment of osteogenic and immune response pathways upon DMP1 stimulation. Results from this study indicate a novel role for DMP1 and GRP78 in modulating immune signaling cascades in PDLSCs.