# Porphyromonas gingivalis-derived extracellular vesicles aggravate bone destruction in rheumatoid arthritis by promoting Syk-dependent osteoclastogenesis

## TL;DR

This study shows that bacteria from the mouth can worsen rheumatoid arthritis by increasing bone destruction through a specific protein pathway.

## Contribution

The study identifies a novel mechanism by which Porphyromonas gingivalis extracellular vesicles exacerbate rheumatoid arthritis via Syk-dependent osteoclastogenesis.

## Key findings

- Porphyromonas gingivalis-derived extracellular vesicles promote osteoclastogenesis and bone destruction in rheumatoid arthritis.
- Pg EVs induce osteoclastogenesis by promoting the phosphorylation of spleen tyrosine kinase (Syk).
- Inhibiting Syk significantly reduces Pg EV-induced osteoclastogenesis and bone destruction in RA.

## Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder that triggers progressive joint destruction by inducing excessive osteoclastogenesis. Porphyromonas gingivalis (Pg), the main pathogenic bacterium involved in periodontitis (PD), is closely related to RA. Pg can secrete extracellular vesicles (EVs), which carry numerous virulence factors. The aim of this study was to investigate whether Pg-derived EVs can be transported and exacerbate bone destruction in RA by promoting osteoclastogenesis and to elucidate the underlying mechanisms involved. EVs derived from Porphyromonas endodontalis (Pe), which is weakly associated with PD or RA, were used as controls. Pg and Pe EVs interact with osteoclasts after translocating into the marrow and metacarpal joints of mice. In vitro, Pg EVs induce osteoclastogenesis via various components, such as lipopolysaccharide, proteins, lipoproteins, and proteases. TNF-α, IL-1β, and IL-6 promote but cannot independently control Pg EV-induced osteoclastogenesis. RNA sequencing and verification experiments further demonstrated that Pg EVs induced osteoclastogenesis by promoting the phosphorylation of spleen tyrosine kinase (Syk). In vivo, Pg EVs exacerbated RA-induced bone destruction by activating Syk-dependent osteoclastogenesis. R406, a Syk inhibitor, significantly attenuated Pg EV-induced RA osteoclastogenesis and bone destruction. However, Pe-derived EVs presented an extremely weak ability to promote osteoclastogenesis and RA. Our findings reveal a new mechanism by which Pg EVs can exacerbate RA via transport through the circulation and the promote Syk-dependent osteoclastogenesis. This study deepens our understanding of the significant pathogenic role of EVs derived from oral bacterial in RA and explores targeted therapeutic strategies by inhibiting the activation of Syk.