Active MMP-9 Levels May Serve as Marker of Behavior, Mood in Fragile X

Choosing best method to measure enzyme may aid diagnosis, treatment, research shows

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An enzyme called matrix metalloproteinase 9 (MMP-9) is found at higher levels in the blood of people with fragile X syndrome than healthy people and may correlate with more aberrant behavior and anxiety-related symptoms, a study reported.

Researchers determined total levels of MMP-9 and of its active form, but the test measuring the active form was a more sensitive method to detect differences between people with and without fragile X syndrome, and monitor disease symptoms.

These results showcase the importance of choosing the appropriate method to measure MMP-9, which can aid in diagnosis and assess behavioral treatment responses in future clinical studies, according to the researchers.

The study, “Clinical significance of matrix metalloproteinase-9 in Fragile X Syndrome,” was published in Scientific Reports.

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Fragile X syndrome is marked by mutations in the FMR1 gene, which provides instructions to make a protein called FMRP. Because FMRP controls protein production in nerve cells, its deficiency leads to the excessive production of certain proteins, disrupting nerve function and communication.

MMP-9 is an enzyme in nerve cells that degrades collagen in the extracellular matrix, a three-dimensional network of proteins and other molecules that surround, support, and give structure to cells. This protein is tightly controlled by FMRP, and therefore people with fragile X often have high MMP-9 levels.

Tests to accurately measure MMP-9 in the bloodstream of fragile X patients may support its diagnosis, and help monitor disease progression and treatment response. However, the clinical utility of MMP-9 measurement in fragile X remains unclear because different methods used to detect MMP-9 have generated different results.

Correlations between MMP-9 levels, behavior

Researchers at the Université de Sherbrooke, Québec, Canada compared two methods of MMP-9 detection to find out which best matched clinical profiles and distinguished people with and without fragile X.

MMP-9 has two forms — an active form with the ability to degrade collagen and an inactive, precursor form that must first be cleaved before turning into the active enzyme.

One of the methods, called enzyme-linked immunosorbent assay (ELISA), assesses the total levels of MMP-9 (active and inactive). The other, gelatin-based zymography, assesses the active enzyme amount.

Blood samples were collected from 23 people with fragile X, ages 17–41, and 20 healthy people, ages 20–41. There were more males than females in the fragile X group than in the healthy control group (87% vs. 57%).

Both methods generated strongly correlated measurements at concentrations lower than 0.5 mg/L, analysis showed. After that, there was a statistically significant difference between the two methods.

Because MMP-9 plasma levels in the bloodstream are influenced by age, sex, and body mass index (a measure of body fat), the team compared a subgroup of 12 fragile X patients to 12 controls who were matched for all these variables.

With gel zymography, the concentration of active MMP-9 was significantly higher in the subgroup of fragile X patients compared with matched controls (0.48 vs. 0.27 mg/L). Total MMP-9 levels assessed with ELISA were not different between the two groups, however.

In patients, higher levels of active MMP-9 also significantly correlated with more aberrant behavior, as assessed with the Aberrant Behavior Checklist Fragile X Adapted Version (ABC-CFX). A significant correlation was obtained between MMP-9 levels and four of the six ABC-CFX subdomains: hyperactivity, social unresponsiveness, inappropriate speech, and stereotypy (repetitive movements or utterances).

Levels of active MMP-9 also significantly correlated with the scores on the Anxiety Depression and Mood Scale (ADAMS) questionnaire, which assesses symptoms of anxiety and depression in people with intellectual disabilities.

In comparison, the socially unresponsive subdomain scores in ABC-CFX were the only significant association with the ELISA test results.

“Our results highlight the importance of choosing the appropriate method to quantify plasma MMP-9 in [fragile X syndrome] studies, specifically in future clinical trials where MMP-9 might be used as a measure of outcomes,” the researchers said. “Gel zymography seems to be a more sensitive method to detect differences in MMP-9 active form between [fragile X syndrome] and healthy controls as well as the association with aberrant behavior, and anxiety related symptoms.”