Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis

by Selleckchem | Jul 20 2023

Elevated osteoclast (OC)-mediated bone resorption, a common pathological feature between periodontitis and rheumatoid arthritis (RA), implicates a possible mutually shared pathogenesis. The autoantibody to citrullinated vimentin (CV), a representative biomarker of RA, is reported to promote osteoclastogenesis (OC-genesis). However, its effect on OC-genesis in the context of periodontitis remains to be elucidated. In an in vitro experiment, the addition of exogenous CV upregulated the development of Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear OCs from mouse bone marrow cells and increased the formation of resorption pits. However, Cl-amidine, an irreversible pan-peptidyl arginine deiminase (PAD) inhibitor, suppressed the production and secretion of CV from RANKL-stimulated OC precursors, suggesting that the citrullination of vimentin occurs in OC precursors. On the other hand, the anti-vimentin neutralizing antibody suppressed in vitro Receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced OC-genesis. The CV-induced upregulation of OC-genesis was abrogated by the Protein kinase C (PKC)-δ inhibitor Rottlerin, accompanied by the downmodulation of OC-genesis-related genes, including Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP and Matrix Metallopeptidase 9 (MMP9) as well as extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. Elevated levels of soluble CV and vimentin-bearing mononuclear cells were found in the bone resorption lesions of periodontitis induced in mice in the absence of an anti-CV antibody. Finally, local injection of anti-vimentin neutralizing antibody suppressed the periodontal bone loss induced in mice. Collectively, these results indicated that the extracellular release of CV promoted OC-genesis and bone resorption in periodontitis.

Comments:

The passage you provided discusses a possible connection between periodontitis and rheumatoid arthritis (RA) through elevated osteoclast-mediated bone resorption. Osteoclasts are cells responsible for breaking down and resorbing bone tissue. The presence of autoantibodies to citrullinated vimentin (CV), a biomarker associated with RA, has been found to promote the development of osteoclasts (osteoclastogenesis). The effect of CV on osteoclastogenesis in the context of periodontitis, however, has not been fully understood.

In an in vitro experiment using mouse bone marrow cells, the addition of exogenous CV was found to enhance the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and increase the formation of resorption pits. This suggests that CV can stimulate the generation of osteoclasts and contribute to bone resorption. The production and secretion of CV from osteoclast precursor cells were inhibited by Cl-amidine, a pan-peptidyl arginine deiminase (PAD) inhibitor. This implies that the citrullination of vimentin occurs in the precursor cells of osteoclasts.

Furthermore, an anti-vimentin neutralizing antibody was found to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa-Β ligand (RANKL) in vitro. RANKL is a protein that plays a crucial role in osteoclast differentiation and activation. The upregulation of osteoclastogenesis by CV was reversed when treated with Rottlerin, a Protein kinase C (PKC)-δ inhibitor. This treatment also led to a decrease in the expression of osteoclastogenesis-related genes such as Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP, and Matrix Metallopeptidase 9 (MMP9), as well as a reduction in extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. These findings suggest that the release of CV outside the cells promotes osteoclastogenesis and bone resorption in periodontitis.

The study also examined bone resorption lesions in mice with induced periodontitis and found elevated levels of soluble CV and mononuclear cells containing vimentin. Furthermore, local injection of an anti-vimentin neutralizing antibody was able to suppress periodontal bone loss in mice. These results indicate that the extracellular release of CV contributes to osteoclastogenesis and bone resorption in periodontitis.

In summary, the passage suggests that CV, an autoantibody associated with RA, can promote osteoclastogenesis and bone resorption in the context of periodontitis. The findings support the idea of a shared pathogenesis between periodontitis and RA, involving the role of osteoclasts and the release of CV.