Differential Expression of Matrix Metalloproteinases in the Serum of Patients with Mucopolysaccharidoses

Abstract

Mucopolysaccharidoses (MPS) represent a heterogeneous group of hereditary disorders, characterized by accumulation of glycosaminoglycans within the lysosomes. The objective of this study was to elucidate the expression and activity of matrix metalloproteinases (MMPs) in the serum of pediatric patients with MPS. Serum gelatinase activity was assessed by gelatin zymography and the concentration of circulating MMP-2, MMP-9, and of tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 was measured by ELISA in the serum of seven patients with MPS (five with MPS III, 1 with MPS II and 1 with MPS VI), and healthy age-and sexmatched participants. Serum activity and protein levels of MMP-9 were significantly reduced whereas of MMP-2 were significantly increased in patients with MPS III, as compared to controls. There were no significant alterations in serum protein levels of TIMP-1 and TIMP-2 in patients with MPS III, as compared to controls. In MPS II, proMMP-2 activity and protein levels of MMP-2 were significantly increased, as compared to control. In MPS VI, enzyme replacement therapy reduced the activity and protein levels of MMP-9 up to 4 months after the initiation of treatment. The reported alterations in the expression of MMPs in the serum of patients with MPS suggest that these molecules may be used as potential biomarkers for the diagnosis, follow-up and response to therapy in patients with MPS.

Free urinary glycosylated hydroxylysine as an indicator of altered collagen degradation in the mucopolysaccharidoses

“…Glycosylated collagen however seems to have a more specific mechanism of intracellular degradation mediated by the uPARAP/Endo180 receptor . Disturbance of the extracellular matrix breakdown in MPS disorders has been described by the observation of altered levels and tissue distribution of cathepsins and matrix metalloproteases in MPS disease models and patients . This study indicates that the intracellular breakdown of collagen is also affected, but not necessarily as a result of lysosome dysfunction; elevated levels of glycosylated hydroxylysine suggest an increase in lysosomal collagen breakdown.…”

“…Further understanding of how accumulated GAGs cause the resulting pathology is needed. One key early pathological feature is the disruption of the ECM . The resulting consequence of this disruption needs to be further understood.…”

“…Samples were analyzed as described previously. 5 The collagen-derived amino acids Lys, Lys-OH, Lys-O-GalGlc and Lys-O-Gal, and internal standard 13 Supplementary Table S2). The capillary voltage was maintained at 3.7 kV, with source temperature held constant at 150 C and nitrogen used as the nebulizing gas at a flow rate of 30 L/ h. FMOC-derivatized amino acids were separated using an ACQUITY UPLC 2.1 × 50 mm BEH C8 1.7-μm column (Waters Corp).…”

Extracellular matrix components: An intricate network of possible biomarkers for lysosomal storage disorders?

“…Given the fact that alterations in circulating levels of gelatinases have been demonstrated in Alzheimer's disease [137,138], in combination with the finding that an over production of these enzymes is coupled with an increased permeability of the blood–brain‐barrier [139], those ECM molecules could possibly represent BMs demonstrating CNS involvement. In relation to treatment responsiveness, we have additionally demonstrated alterations in circulating levels and enzyme activity of gelatinases in an MPS VI patient under ERT, classifying these molecules as possible candidates for follow‐up markers [136].…”

“…In addition, it was shown that the expression of MMP‐1 is decreased in human pluripotent stem cells which were generated from skin fibroblasts of MPS IIIB children [102]. We have recently demonstrated that gelatinase expression is altered in the serum of various types of MPS patients [136]. MMP‐2 was significantly increased concerning both the enzyme activity and circulating levels, while a decrease in gelatinolytic activity and serum expression of MMP‐9 was observed.…”