proBDNF-SorCS2 Axis Suppresses Osteogenesis and Augments Inflammation of Human Periodontal Ligament Stem Cells in Inflammatory Conditions.

OBJECTIVES: Periodontitis is a chronic inflammatory disease occurring in periodontal supporting tissues. Periodontal ligament stem cells (PDLSCs) are considered a promising source for periodontal regeneration and periodontitis treatment. Previous studies have shown that mature brain-derived neurotrophic factor (BDNF) can promote the multidirectional differentiation potential of PDLSCs. It has also been found that the proBDNF (precursor form of BDNF)-mediated signaling pathway is involved in immune-inflammatory diseases. In addition, some scholars have found that proBDNF and its receptor, sortilin-related central nervous system expressed receptor 2 (SorSC2), can induce cell apoptosis. However, the role of the proBDNF-SorCS2 axis in the development of periodontitis and its influence on human periodontal ligament stem cells (hPDLSCs) has not been elucidated. Our present experiment aims to investigate the relationship between the proBDNF-SorCS2 axis and periodontitis, as well as the role of proBDNF-SorCS2 in the osteogenic differentiation of hPDLSCs. METHODS: In this study, 30 patients with periodontitis (PD) and 30 healthy controls (Cont) were selected to detect the protein expression level and the distribution of the proBDNF-SorCS2 axis in periodontal tissues. In addition, an inflammatory model of hPDLSCs was established to study the regulation of SorCS2 expression on inflammation and cell osteoblastic differentiation. RESULTS: In our experimental results, we found that the protein expressions of proBDNF and receptor SorCS2 were significantly increased in periodontitis tissues and colocalized with the hPDLSC surface marker CD90. Importantly, we found that the reduction of SorCS2 in hPDLSCs inhibited the protein activity of the proBDNF-SorCS2 signaling axis, IL-6, and IL-1β, promoting osteogenic differentiation of hPDLSCs. We also note that the proBDNF-SorCS2 signaling axis is involved in the activation of the JNK signaling pathway. CONCLUSION: The protein levels of both proBDNF and its receptor SorCS2 were significantly upregulated in periodontitis tissues and involved in regulating the inflammatory expression level and osteogenic differentiation of hPDLSCs. The proBDNF-SorCS2 axis represents a promising target for novel, localized therapeutic interventions in periodontitis. CLINICAL RELEVANCE: The current study provides a new theoretical perspective and information for the treatment of periodontitis.