Abstract
Periodontitis is a chronic inflammatory disease with alveolar bone resorption and subsequent tooth loss as its ultimate outcomes. Gastrin-releasing peptide (GRP) is a neuropeptide with growth-stimulatory and tumorigenic properties, and neuropeptides have previously been suggested to play a role in the complex cascade of chemical activity associated with periodontal inflammation. In this study, GRP treatment enhanced the differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts, and gastrin-releasing peptide receptor (GRPR) antagonists suppressed the pro-osteoclastogenic effect of GRP. Grpr-siRNA knockdown resulted in a significantly lower number of osteoclasts formed as compared with the control. Interestingly, gene expression analysis indicated downregulation of Grp and Grpr expressions in BMMs during osteoclastogenesis. Moreover, ligature-induced periodontitis model in mice and gingival samples from patients with periodontitis displayed increased immunostaining of GRP in the oral epithelium. Subsequently, stimulation of mouse primary epithelial cells (ECs) and HaCaT cells, human epidermal keratinocytes, with lipopolysaccharides (LPS) of Porphyromonas gingivalis or live P. gingivalis upregulated Grp and Grpr expressions. Finally, coculture of P. gingivalis-stimulated ECs and BMMs using Transwell system revealed that the differentiation of BMMs was induced when subjected to paracrine activation by LPS- as well as live-P. gingivalis stimulated ECs. Taken together, our results demonstrate that the pro-osteoclastogenic properties of BMMs may be modulated by GRP produced by ECs in the periodontal microenvironment.
Highlights
Periodontitis is one of the most prevalent chronic inflammatory diseases initiated by bacteria and progressed by individual’s host inflammatory response to a dysbiotic microbial biofilm on tooth surfaces [1]
We focused on ECs to explore their potential supporting effeIcnt othnetfhoellooswteioncglaasntoaglyesneess,iws oeffoBcMuMsesd. oEnCsECwsertoe estxipmlourlaettehdeibrypLoPteSnotifaPl .sugipnpgoivratilnisg(1 1(e10ffotfio0oreor,rcn1tf201o4io0nrμnhcμg2.rgt/4eCmh/aheomsL.neo)LdssCoi)tsrteoothoeinrnencsoiltineascwxsotuetpclionautrghtetleesawrdsnteeieioswdtsuhniilwsttrohseoiftfslfhirGuvoBllremtiMpvsPeMaFf.rnPigogs.di.mnuggrGiEneiFvCrgip4agisrl,viuLsawirlnPaieestSrm4ames,totsuiLmutmliPstmuieuSplultleasiilppcttaiiilitomtiteychnduieotalylbfainatyiodnilofLfcPnieePn.clfaSgtleisnioncod(ntgfFiio(PiPvgMn..aulgg(OirMsiiennIi)ggnO5oiioAvvIfc)aa)1ullo.ii0lssfIa0n, inoculation increased the expression of Grp and Grpr in mouse epithelial cells (Figure 5A)
We report a unique function for Gastrin-releasing peptide (GRP) and its receptor gastrin-releasing peptide receptor (GRPR) in manifesting increased differentiation of bone marrow-derived macrophages (BMMs)
Summary
Periodontitis is one of the most prevalent chronic inflammatory diseases initiated by bacteria and progressed by individual’s host inflammatory response to a dysbiotic microbial biofilm on tooth surfaces [1]. Periodontitis is a slowly progressing disease, but the destruction of the supporting tissues around the teeth, gingiva, periodontal ligament, and alveolar bone, is largely irreversible. GRP is a mammalian homolog of bombesin (BN), a tetradecapeptide originally isolated from frog skin [6] and a part of the bombesin-like peptide (BLP) family that binds to the same receptor of the amphibian bombesin peptide [7]. Four BLP binding receptor subtypes have been isolated so far. Receptor subtype 1 binds neuromedin B and receptor subtype 2, termed GRPR, binds BN and GRP with high affinity. Receptor subtype 3 is an orphan receptor whose ligand has not been identified yet, and subtype 4 binds BN and GRP with high and low affinities, respectively [5]. GRPR is the most widely expressed BLP-binding receptor subtype in human tissues
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