Increased acinar damage of salivary glands of patients with Sjögren's syndrome is paralleled by simultaneous imbalance of matrix metalloproteinase 3/tissue inhibitor of metalloproteinases 1 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 ratios

Abstract

Objective. Previous findings in labial salivary glands (LSGs) from patients with Sjögren's syndrome (SS) suggest that increased activity and expression of matrix metalloproteinase 9 (MMP-9) and MMP-3 trigger the destruction of acinar structures in these glands. Tissue inhibitors of matrix metalloproteinases (TIMPs) tightly control MMP activity, and TIMP expression is an important modulator of effects attributed to MMPs. This study was undertaken to investigate the correlation between the balance of MMPs/TIMPs in the LSGs of SS patients and the degree of inflammatory infiltration and acinar structure integrity.Methods. Three groups of SS patients classified according to focus score and residual tissue were studied. The expression of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 was examined at the messenger RNA and protein levels. The ratio of MMP/TIMP expression (R value) was calculated. Focus score and acinar structure were evaluated by histologic analysis.Results. In SS patients the MMP-3/TIMP-1 ratio was higher than 1 and the MMP-9/TIMP-1 ratio was much higher than 1 whereas the MMP-2/TIMP-2 ratio nearly equaled 1, suggesting elevated proteolytic activity due mainly to MMP-9. R values were independent of the focus score of inflammatory cells, but correlated well with the dramatic changes observed in morphologic integrity of acini, as revealed mainly by the lack of nuclear polarity. Acinar changes were more evident when R values for both MMP-9/TIMP-1 and MMP-3/ TIMP-1 were higher.Conclusion. This study provides evidence that an altered balance between MMPs and their inhibitors is associated with acinar damage. Since salivary gland acinar cells express both MMPs and TIMPs, these cells may play an important role in extracellular matrix destruction and in the LSG pathophysiology in SS.Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a key role in tissue-remodeling events under both normal and pathologic conditions (1). Their expression is regulated by growth factors, cytokines, and hormones, as well as by interactions with extracellular matrix (ECM) proteins (1). Endogenous inhibitors, such as tissue inhibitors of matrix metalloproteinases (TIMPs), also exist to counterbalance MMP activity (2).To date, 4 TIMP family members have been described. TIMPs 1, 2, and 4 are secreted as soluble proteins, whereas TIMP-3 is associated with matrix components as an insoluble protein (3).

Human chorionic gonadotropin prevents Sjögren's syndrome–like exocrinopathy in mice

“…Expression of the mRNA transcripts for the proinflammatory cytokines IFN␥, TNF␣, IL-1␤, IL-10, and iNOS was significantly decreased in the submandibular glands of HCG-treated mice as compared with PBS-treated mice (Figure 2A). Similarly, the expression of MMP-9, which is known to be involved in the activation of apoptosis and glandular damage (13), was significantly reduced in HCG-treated mice. HCG treatment also depressed stimulated production of the Th1 cytokine, IFN␥, from mouse spleen cells and enhanced production of the Th2 cytokine, IL-4 ( Figure 2B).…”

Infantile Chronic Recurrent Parotitis (ICRP): Analysis of Changes in the Expression of Parotid Salivary Proteins Associated with the Disease

“…Hystolochemical studies on slices of parotid and submandibular glands indicate that MMP-2 and MMP-9 would be mostly located in the duct system and absent from the acinar system (Ogbureke & Fisher, 2004;Nagel et al, 2004;Teymoortash et al, 2004). Similar studies on lip salivary glands have shown the presence of MMP-2 and MMP-9 in duct cells and at the basal region of acinar cells (Pérez et al, 2000(Pérez et al, , 2005. These observations would suggest that those molecules would not be released from the gland to the oral cavity under normal conditions.…”

“…Patients with Sjögren's syndrome have an increased activity of MMP-9 in saliva as well as an altered MMP-9 / TIMP-1 (a tissular inhibidor of MMPs 1) ratio, as compared to healthy control subjects (Asatsuma et al, 2004;Hanemaaijer et al, 1998;Wu et al, 1997). More recent studies in biopsies of minor salivary glands of patients with Sjögren's síndrome have shown alterations in tissular metalloproteinases that coincide with those observed in saliva (Pérez et al, 2005).…”

<b>Pivotal role of duct epithelia in salivary gland </b><b>GVHD </b>

“…Although exact mechanism is unknown, there are reduction of the acinar parenchyma while intraglandular ducts exhibit hyperplasia of the lining cells in Sjögren's syndrome (Barone et al, 2015). And factors like metalloproteinases are also reported to affect susceptibility of acini (Perez et al, 2005). These facts suggest that acinar cells are more susceptible to tissue injury than ductal cells in inflammatory diseases.…”