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Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood\u2010brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real\u2010time polymerase chain reaction (RT\u2010PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti\u2010inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber\u2010derived astroglial cultures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL\u20101\u03b2\u2010induced dysregulation of<jats:italic>MMP3<\/jats:italic>,<jats:italic>TIMP2<\/jats:italic>,<jats:italic>TIMP3 and TIMP4<\/jats:italic>could be rescued by miR146a and miR147b in tuber\u2010derived TSC cultures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study provides evidence of dysregulation of the MMP\/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated<jats:italic>in vitro<\/jats:italic>by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12572","type":"journal-article","created":{"date-parts":[[2019,6,10]],"date-time":"2019-06-10T19:08:49Z","timestamp":1560193729000},"page":"142-159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Increased matrix metalloproteinases expression in tuberous sclerosis complex: modulation by microRNA 146a and 147b<i>in vitro<\/i>"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4842-0659","authenticated-orcid":false,"given":"D. W. 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E.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. G.","family":"Spliet","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. C.","family":"van Rijen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Rudolf Magnus Institute for Neuroscience University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. 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