Cystathionine γ-lyase contributes to exacerbation of periodontal destruction in experimental periodontitis under hyperglycemia

Background: Diabetes is one of the major inflammatory comorbidities of periodontitis via 2-way interactions. Cystathionine γ-lyase (CTH) is a pivotal endogenous Enzyme synthesizing hydrogen sulfide (H₂S), and CTH/H₂S is crucially implicated in modulating inflammation in various diseases. This study aimed to explore the potential role of CTH in experimental periodontitis under a hyperglycemic condition.

Methods: CTH-silenced and normal human periodontal ligament cells (hPDLCs) were cultured in a high glucose and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) condition. The effects of CTH on hPDLCs were assessed by Cell Counting Kit 8 (CCK8), real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The model of experimental periodontitis under hyperglycemia was established on both Cth^-/- and wild-type (WT) mice, and the extent of periodontal destruction was assessed by micro-CT, histology, RNA-Seq, Western blot, tartrate-resistant Acid Phosphatase (TRAP) staining and immunostaining.

Results: CTH mRNA expression increased in hPDLCs in response to increasing concentration of P.g-LPS stimulation in a high glucose medium. With reference to WT mice, Cth^-/- mice with experimental periodontitis under hyperglycemia exhibited reduced bone loss, decreased leukocyte infiltration and hindered osteoclast formation, along with reduced expression of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in periodontal tissue. RNA-seq-enriched altered NF-κB pathway signaling in healthy murine gingiva with experimental periodontitis mice under hyperglycemia. Accordingly, phosphorylation of p65 (P-p65) was alleviated in CTH-silenced hPDLCs, leading to decreased expression of IL6 and TNF. CTH knockdown inhibited activation of nuclear factor kappa-B (NF-κB) pathway and decreased production of proinflammatory cytokines under high glucose and P.g-LPS treatment.

Conclusion: The present findings suggest the potential of CTH as a therapeutic target for tackling periodontitis in diabetic patients.

cystathionine gamma‐lyase; diabetes mellitus; hyperglycemia; inflammation; periodontitis.