MZB1 Drives Periodontitis via ER Stress-Mediated Inflammation and Osteogenic Differentiation

Introduction and aims: Increasing evidence suggests that marginal zone B and B1 cell-specific protein (MZB1) plays crucial roles in inflammatory responses, endoplasmic reticulum (ER) stress, and cell survival, but its function in periodontitis is still unclear. Periodontitis is a chronic inflammatory disease. This study aimed to investigate the expression profile and functional role of MZB1 in periodontitis. Methods: Transcriptomic analysis and RT-qPCR were performed to evaluate MZB1 expression in gingival tissues of periodontitis patients. An in vitro inflammatory model of periodontal ligament stem cells (PDLSCs) was established using lipopolysaccharide (LPS), and an in vivo rat periodontitis model was constructed. Loss-of-function assays were conducted via shRNA or adeno-associated virus (AAV)-mediated knockdown of MZB1. The effects of MZB1 knockdown on cell proliferation, apoptosis, ER stress, and osteogenic differentiation were assessed. Results: Transcriptomic analysis revealed that MZB1 was significantly upregulated in gingival tissues of periodontitis patients and enriched in inflammation-related pathways. Knockdown of MZB1 alleviated LPS-induced damage in PDLSCs, improved cell viability and proliferation, reduced ER stress and apoptosis. Moreover, MZB1 depletion significantly restored the osteogenic differentiation potential of PDLSCs, as evidenced by increased mineralised nodule formation, alkaline phosphatase (ALP) activity, and elevated expression of osteogenesis-related proteins (RUNX2, BMP2, and Collagen I). In vivo, AAV-mediated MZB1 knockdown ameliorated periodontal inflammation, tissue destruction, and functional impairment. Conclusion: MZB1 downregulation alleviates inflammation, suppresses ER stress and apoptosis, and enhances the osteogenic capacity of PDLSCs, indicating that MZB1 plays a crucial role in the development and progression of periodontitis. Clinical Relevance: Targeting MZB1 represents a promising therapeutic strategy. Inhibiting MZB1 could alleviate ER stress, enhance bone regeneration, and restore periodontal tissue homeostasis, potentially leading to more effective and regenerative treatments for periodontitis.