Differential expression of matrix metalloproteinases in labial salivary glands of patients with primary Sjögren's syndrome.

Abstract

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 Sjogren's syndrome (primary SS). 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. 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. 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.