Inhibition of transglutaminase activity in periodontitis rescues periodontal ligament collagen content and architecture

Abstract

Background and objective Periodontal disease (PD) afflicts approximately 50% of the population in the United States and is characterized by chronic inflammation of the periodontium that can lead to loss of the periodontal ligament through collagen degradation, loss of alveolar bone, and to eventual tooth loss. Previous studies have implicated transglutaminase (TG) activity in promoting thin collagen I fiber morphology and decreased mechanical strength in homeostatic PDL. The aim of this study was to determine whether TG activity influenced collagen assembly in PDL in the setting of periodontal disease. Material and methods A ligature model was used to induce clinically relevant PD in mice. Mice with ligature were assessed at 5 and 14 days to determine PDL collagen morphology, transglutaminase (TG) activity, and bone loss. The effects of inhibition of TG on PDL were assessed by immunohistochemistry and second‐harmonic generation (SHG) to visualize collagen fibers in native tissue. Results Ligature placement around the 2nd molar resulted in significant bone loss and a decrease in total collagen content after 5 days of ligature placement. A significant increase in thin over thick fibers was also demonstrated in mice with ligature at 5 days associated with apparent increases in immunoreactivity for TG2 and for TG‐mediated N‐ε‐γ‐glutamyl cross‐links in PDL. Inhibition of TG activity increased total collagen and thick collagen fiber content over vehicle control in mice with ligature for 5 days. SHG of PDL was used to visualize and quantify the effects of TG inhibition on enhanced collagen fiber organization in unfixed control and diseased PDL. Conclusion These studies support a role of TG in regulating collagen fiber assembly and suggest that strategies to inhibit TG activity in disease might contribute to restoration of PDL tissue integrity.

Pten regulates collagen fibrillogenesis by fibroblasts through SPARC

“…Collagen shuttling may be dependent on hydroxylation by P4HA3, as we observed significant upregulation of mRNA expression of this enzyme in the PTEN null cells. Another potential mechanism by which SPARC may regulate collagen deposition is by modulating the activity of transglutaminases, a family of proteins involved in extracellular collagen fiber assembly [ 53 ]. In dental tissue, transglutaminase crosslinking of collagen was found to be greater in SPARC‐null tissues in comparison to WT, suggesting that SPARC bound to collagen may reduce accessibility of collagen to TG modification [ 54 ].…”

Nonuniformity in Periodontal Ligament: Mechanics and Matrix Composition

“…There are 2 types of crosslinks in the PDL, reducible and irreducible, which contribute differently to tissue stiffness and resistance to degradation (Kaku et al 2016). Crosslinked collagen fibers usually increase tissue stiffness, but high LOX and TGM presence might also be indicative of high tissue damage and remodeling rate and smaller-sized fiber production, as seen in periodontal disease (Moore Rosset et al 2020). The furcation region incurs high and repetitive compression forces that can cause tissue damage and therefore requires rapid remodeling.…”

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

“…Additionally, thin fibers were significantly increased in ligated mice at 5 and 14 days, suggesting the promotion of collagen fiber remodeling in the PDL of periodontitis mice. However, inhibition of transglutaminase (TG) activity that has been indicated to regulate collagen fiber formation [74] increased total collagen and thick collagen fiber content in the group with ligation at 5 days [75].…”