Differential expression of matrix metalloproteinases in labial salivary glands of patients with primary Sjögren's syndrome: Mechanisms of exocrine parenchyma destruction

Abstract

Objective To determine the enzymatic activity and cellular localization of matrix metalloproteinases (MMPs) 2, 3, and 9 in labial salivary glands from patients with different degrees of severity of primary Sjögren's syndrome (primary SS). Methods Gelatinase activity was determined by zymography and quantified by densitometry. The specificity of MMPs was determined using protease inhibitors and chelators, as well as activators of the latent forms of these enzymes. The cellular localization of MMPs was carried out using monoclonal antibodies that recognize their latent and active forms. Results Labial glands from control subjects and patients showed gelatinase activity for MMP‐2 and MMP‐9. Activation studies revealed that both enzymes were predominantly present in their latent forms. The highest levels of MMP‐9 activity were detected in patients with severe, active, primary SS (except for patients with severe clinical symptoms for extended periods) and correlated with structural and functional glandular changes. MMP‐2 activity was almost the same in patients and controls. MMPs were detected by immunolocalization only in acinar and ductal cells and were homogeneously distributed throughout patients' glands. MMP‐2 and MMP‐9 expression paralleled their gelatinase activity. MMP‐3, detectable only with immunologic methods, was absent in control subjects but abundantly expressed in patients. Importantly, MMP protein levels in acinar and ductal cells were independent of either the presence or the proximity of mononuclear infiltrate cells. Conclusion MMP‐3 and MMP‐9 expression, as well as MMP‐9 catalytic activity, were increased in tissue samples from SS patients in a manner that correlated with the severity of the disease. Most important, increased MMP activity stemmed from exocrine epithelial cells and was not due to infiltrating lymphocytes. Thus, changes in salivary glands as a consequence of proteolysis may lead to severe glandular destruction.

Animal Models of Sjögren’s Syndrome

“…This has also been described in human minor salivary glands [42,43]. Furthermore, we recently described elevated levels of soluble E-cadherin in serum of patients with primary SS [44] potentially related to increased MMP-mediated cleavage and lymphocyte attraction to the target organ.…”

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

“…33 MMP-9 activity levels are increased in salivary glands from patients with Sjögren's syndrome compared to normal controls. 34 The mRNA expression of MMP-9 is increased in the skin of the lupus prone MRLlpr mice during disease development, with highest levels of expression in skin with lupus-like involvement and dermal immune complex deposition. 35 A second associated connective tissue-related gene found to be hypomethylated in lupus CD4 + T cells is platelet-derived growth factor receptor alpha (PDGFRA).…”

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

“…Elevation in MMP concentration in the saliva from patients with SS may be responsible for the increased remodeling of basement membrane proteins, such as laminin, and/or structural destruction of the basement membrane scaffolding in salivary glands in SS (Konttinen et al ., 1998). Indeed, recent analysis of MMP-9 activity in gland biopsy material has provided evidence for the production of proteases in acinar cells of salivary glands removed from sites of lymphocytic foci (Pérez et al ., 2000). Additionally, higher levels of MMP activity correlated with more severe histopathology.…”