Gram-positive bacteria cell wall-derived lipoteichoic acid induces inflammatory alveolar bone loss through prostaglandin E production in osteoblasts

Tsukasa Tominari,Yoshifumi Itoh,Michiko Hirata,Yukihiro Numabe,Chiho Matsumoto,Ryota Ichimaru,Chisato Miyaura,Ayumi Sanada,Masaki Inada

doi:10.1038/s41598-021-92744-5

Abstract

Periodontitis is an inflammatory disease associated with severe alveolar bone loss and is dominantly induced by lipopolysaccharide from Gram-negative bacteria; however, the role of Gram-positive bacteria in periodontal bone resorption remains unclear. In this study, we examined the effects of lipoteichoic acid (LTA), a major cell-wall factor of Gram-positive bacteria, on the progression of inflammatory alveolar bone loss in a model of periodontitis. In coculture of mouse primary osteoblasts and bone marrow cells, LTA induced osteoclast differentiation in a dose-dependent manner. LTA enhanced the production of PGE2 accompanying the upregulation of the mRNA expression of mPGES-1, COX-2 and RANKL in osteoblasts. The addition of indomethacin effectively blocked the LTA-induced osteoclast differentiation by suppressing the production of PGE2. Using ex vivo organ cultures of mouse alveolar bone, we found that LTA induced alveolar bone resorption and that this was suppressed by indomethacin. In an experimental model of periodontitis, LTA was locally injected into the mouse lower gingiva, and we clearly detected alveolar bone destruction using 3D-μCT. We herein demonstrate a new concept indicating that Gram-positive bacteria in addition to Gram-negative bacteria are associated with the progression of periodontal bone loss.

Highlights

Periodontitis is a local infectious disease associated with inflammatory alveolar bone loss
We have reported that LPS and pro-inflammatory factors, including interleukin-1α enhance the membrane-bound PGE synthase (mPGES)-1-mediated production of P GE2 and the RANKL expression in osteoblasts, leading to osteoclastogenesis and inflammatory bone r esorption[1,8,9,10]
Lipoteichoic acid (LTA) is a ligand of TLR2/6 heterodimer, we first examined the mRNA expression of TLR2 and TLR6 in primary osteoblasts (POBs) and osteoclasts by RT-quantitative PCR (qPCR)

Summary

Introduction

Periodontitis is a local infectious disease associated with inflammatory alveolar bone loss. The expression of receptor activator of NF-κB ligand (RANKL) on the cell surface of osteoblasts is essential for osteoclast differentiation[2,3,4]. We have reported that LPS and pro-inflammatory factors, including interleukin-1α enhance the mPGES-1-mediated production of P GE2 and the RANKL expression in osteoblasts, leading to osteoclastogenesis and inflammatory bone r esorption[1,8,9,10]. It is well known that Gram-negative bacteria derived LPS dominantly induces inflammatory alveolar bone destruction; the roles of Gram-positive bacteria cell wall-derived LTA in periodontal bone resorption are remains unclear. Grampositive bacteria may enhance inflammation in periodontitis with alveolar bone loss through the action of LTA

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Results

Conclusion