Inhibition of Endoplasmic Reticulum Stress by 4-Phenyl Butyric Acid Presents Therapeutic Effects on Periodontitis: Experimental Studies In Vitro and in Rats

Abstract

This study investigated the probable mechanisms of endoplasmic reticulum (ER) stress involved in periodontitis <i>in vitro</i> and <i>in vivo</i>. We isolated periodontal ligament stem cells from periodontitis patients and healthy controls (P-PDLSCs and H-PDLSCs). To further simulate the periodontal microenvironment in patients, lipopolysaccharide (LPS) was used to treat H-PDLSCs. The results showed that periodontitis-related inflammation gave rise to the upregulated expression levels of ER stress representative genes including <i>GRP78</i>, <i>PERK</i>, <i>ATF4</i>, and <i>CHOP</i>. In contrast, the treatment of 4-phenyl butyric acid (4-PBA) remarkably suppressed ER stress and supported cell viability. The increased secretion of proinflammatory factors like TNF-<i>α</i>, IL-1<i>β</i>, and IL-6 and the activation of NF-<i>κ</i>B pathway were also attenuated by 4-PBA treatment. Moreover, 4-PBA treatment restored the impaired osteogenic differentiation ability of PDLSCs, as demonstrated by the upregulated expression levels of Runx2 and OCN as well as the enhanced Alizarin red staining. Local administration of 4-PBA could rescue alveolar bone resorption of LPS-induced periodontitis rats. Thus, our findings suggested ER stress might act as a promising therapeutic target against periodontitis.