Abstract
Matrix metalloproteinase (MMP) dysregulation is implicated in several diseases, given their involvement in extracellular matrix degradation and cell motility. In lymphangioleiomyomatosis (LAM), a pulmonary rare disease, MMP-2 and MMP-9 have been detected at high levels in serum and urine. LAM cells, characterized by a mutation in the tuberous sclerosis complex (TSC)1 or TSC2, promote cystic lung destruction. The role of MMPs in invasive and destructive LAM cell capability has not yet been fully understood. We evaluated MMP-2 and MMP-7 expression, secretion, and activity in primary LAM/TSC cells that bear a TSC2 germline mutation and an epigenetic modification and depend on epidermal growth factor (EGF) for survival. 5-azacytidine restored tuberin expression with a reduction of MMP-2 and MMP-7 levels and inhibits motility, similarly to rapamycin and anti-EGFR antibody. Both drugs reduced MMP-2 and MMP-7 secretion and activity during wound healing and decreased their expression in lung nodules of a LAM mouse model. In LAM/TSC cells, MMP-2 and MMP-7 are dependent on tuberin expression, cellular adhesion, and migration. MMPs appears sensitive to rapamycin and anti-EGFR antibody only during cellular migration. Our data indicate a complex and differential modulation of MMP-2 and MMP-7 in LAM/TSC cells, likely critical for lung parenchyma remodeling during LAM progression.
Highlights
Published: 24 November 2021Matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, is the principal family of enzymes responsible for extracellular matrix (ECM) degradation [1].This event plays a fundamental role in physiological processes, including organ development, tissue remodeling, angiogenesis, inflammation, and wound healing
MMP-2 expression was greatly reduced in LAM/tuberous sclerosis complex (TSC) tuberin-expressing cells compared to control LAM/TSC cells
MMP-7 levels were similar in the two populations, suggesting that MMP-7 expression is independent of tuberin expression (Figure 1A,B)
Summary
Matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, is the principal family of enzymes responsible for extracellular matrix (ECM) degradation [1]. This event plays a fundamental role in physiological processes, including organ development, tissue remodeling, angiogenesis, inflammation, and wound healing. MMPs are either secreted from the cells or anchored to the plasma membrane [3] and their regulation involves both the control of mRNA levels and the cleavage of the zymogen to the active form. Protein secretion and localization are highly controlled, and their function in vivo strongly depends on the presence of specific inhibitors [2].
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