Abstract
Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase implicated in a wide range of inflammatory and neoplastic diseases, including chronic periodontitis, a persistent oral mucosal inflammation attributed primarily to infection by P. gingivalis. Here, we review the signaling pathways engaged by P. gingivalis in controlling the processing and secretion of MMP-9. The induction in oral mucosal expression of MMP-9 by P. gingivalis relays primarily on its key endotoxin, LPS, engagement of TLR4 and the activation of MAPK, ERK and p38 cascades implicated in the stimulation of Rac1 and cPLA2. The ERK-mediated cPLA2 phosphorylation plays an essential role in its membrane translocation with Rac1, while p38 localization with Rac1 promotes cPLA2 activation and the induction in MMP-9. Moreover, the induction in MMP-9 secretion by the LPS and the modulatory influence of peptide hormone, ghrelin, occur at the level of MMP-9 processing between ER and Golgi, with the involvement of factors that control secretory cargo sorting, Arf1 GTPase and PKD2. The secretion of MMP-9, furthermore, occurs in concert with the changes in stability dynamics of microtubules (MTs), which affect the Golgi localization of Arf1 and the recruitment and activation of PKD2. The induction in MMP-9 secretion by LPS is accompanied by the enhancement in MT stabilization and α-tubulin phosphorylation on Ser, while the MT destabilization associated with the modulatory influence of ghrelin, is manifested by α-tubulin phosphorylation on Tyr. Thus, the factors capable of affecting MT dynamics and MMP-9 secretion present a tempting target for the therapeutic intervention in the treatment of chronic periodontitis.
Highlights
Porphyromonas gingivalis, a rod-shaped, Gram-negative anaerobe together with two other oral bacterial species colonizing the oral cavity, Treponema denticola, and Tannerella forsythia, form so called “red bacterial complex” recognized as the primary etiological cause of periodontitis, a chronic inflammatory disease that leads to progressive destruction of teeth-supporting tissue and is the major cause of adult tooth loss [1] [2] [3] [4]
Considering that PKC and Src family tyrosine kinase (SFK) play a major role in propagation of oral mucosal inflammatory response to P. gingivalis associated with the enhancement in Matrix metalloproteinase-9 (MMP-9) production, as well as are the targets of modulatory influence of a peptide hormone, ghrelin [33] [74] [86], we assessed the influence of P. gingivalis LPS and ghrelin on tubulin phosphorylation in salivary gland acinar cells and the Matrix metalloproteinases (MMPs)-9 secretory processes affected by the changes in MT dynamics [87]
The findings revealed that P. gingivalis LPS-elicited induction in the acinar cell MMP-9 secretion is accompanied by the enhancement in MT stabilization, while the modulatory influence of peptide hormone, ghrelin, is associated with MT destabilization Further, we found that the changes in MT dynamics induced by the LPS and ghrelin occur through signal-regulated α-tubulin phosphorylation on Ser/Tyr [87]
Summary
Porphyromonas gingivalis, a rod-shaped, Gram-negative anaerobe together with two other oral bacterial species colonizing the oral cavity, Treponema denticola, and Tannerella forsythia, form so called “red bacterial complex” recognized as the primary etiological cause of periodontitis, a chronic inflammatory disease that leads to progressive destruction of teeth-supporting tissue and is the major cause of adult tooth loss [1] [2] [3] [4]. P. gingivalis, by far the most prominent member of the bacterial flora found in periodontal packets of people with gum disease [12], has to its disposal an impressive array of virulence factors that provoke the inflammatory response of the host tissue [13] [14] These include its cell surface major (FimA) and minor (Mfa1) fimbriae proteins, elaborated arginine and lysine specific cysteine proteinases, referred to as gingipain R and gingipain K [15] [16], collagenases, capable of extracellular matrix proteins degradation and activation of the host matrix metalloproteinases [17] [18] [19], and the secreted sufatases directed towards cell membrane glycosphingolipids as well as proteoglycans of extracellular matrix [3] [20]. Considering that the elevated levels of MMP-9, along with the increased proinflammatory cytokine production are implicated in pathogenesis of chronic periodontitis, in this article we review data on the signaling pathways engaged by periodontopathogen, P. gingivalis, in controlling the processing and secretion of MMP-9
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