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

Abstract

<h3>Background</h3><p>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.</p><h3>Methods</h3><p>CTH-silenced and normal human periodontal ligament cells (hPDLCs) were cultured in a high glucose and <em>Porphyromonas gingivalis</em> lipopolysaccharide (<em>P.g</em>-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 <em>Cth</em>^−/− 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.</p><h3>Results</h3><p><em>CTH</em> mRNA expression increased in hPDLCs in response to increasing concentration of <em>P.g</em>-LPS stimulation in a high glucose medium. With reference to WT mice<em>, Cth</em>^−/− 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 <em>CTH</em>-silenced hPDLCs, leading to decreased expression of <em>IL6</em> and <em>TNF</em>. <em>CTH</em> knockdown inhibited activation of nuclear factor kappa-B (NF-κB) pathway and decreased production of proinflammatory cytokines under high glucose and <em>P.g</em>-LPS treatment.</p><h3>Conclusion</h3><p>The present findings suggest the potential of CTH as a therapeutic target for tackling periodontitis in diabetic patients.</p>