Alterations in matrix metalloproteinase‐9 levels and tissue inhibitor of matrix metalloproteinases‐1 expression in a transforming growth factor‐β transgenic model of hydrocephalus

Abstract

The development of spontaneous hydrocephalus in mouse models resulting from the overexpression of transforming growth factor-beta (TGFbeta-1) has been previously described, although the mechanism by which this occurs remains obscure. It has been previously demonstrated that increased expression of TGFbeta has consequences for the levels of matrix metalloproteinases (MMPs) and their specific inhibitors (tissue inhibitors of MMPs, or TIMPs). These remodeling proteins play an important role in extracellular matrix (ECM) maintenance through degradation and deposition of ECM components. The present study investigated the relationship between elevated levels of TGFbeta-1, the ECM modulators TIMP-1 and MMP-9, and development of hydrocephalus in the neonatal mouse. In newborn pups, TIMP-1 mRNA levels were equal between animals expressing the TGFbeta-1 transgene and littermates without the transgene. However, immunohistochemistry of littermate pups shows that the distribution of TIMP-1 was changed from homogeneous with large punctate concentrations of signal to uniform, dense staining in hydrocephalic animals carrying the TGFbeta-1 transgene. The mRNA levels of MMP-9 were decreased in the transgenic animals, as were the activity levels MMP-9. These results suggest that the remodeling protein MMP-9 and its specific inhibitor, TIMP-1, may contribute to the spontaneous development of hydrocephalus in this transgenic model by altering the ECM environment.

ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

“…Either the overexpression of MMP9 in alveolar macrophages, the induction of MMP12 expression in lung epithelial cells or the loss of Tissue inhibitor of metalloproteinase 3 ( Timp3 ) causes air space enlargement in mouse lungs (Foronjy et al, 2008; Qu et al, 2009; Leco et al, 2001), a prominent phenotype in mice lacking Atxn1L . It is also noteworthy that alterations in MMP levels and ECM formation are closely associated with pathogenesis of hydrocephalus and abdominal wall hernias (Wyss-Coray et al, 1995; Zechel et al, 2002; Antoniou et al, 2009; Suzuki et al, 1996), both highly penetrant in Atxn1L- null mice. Therefore, we set out to confirm the Mmp gene expression changes observed by transcriptional profiling using qRT-PCR.…”

“…The ECM composition in the meninges, where the arachnoid villi are located, is regarded as an important environment for absorption of CSF into arachnoid villi (Zhao et al, 2010). Several studies using genetically engineered mouse models have indicated that alterations in Mmp9 levels are associated with development of hydrocephalus (Zechel et al, 2002; Muñoz et al, 2006; Oshima et al, 1996). Therefore, our finding that Mmp9 levels are up-regulated in the meninges from Atxn1L −/− mice may explain the onset of hydrocephalus in Atxn1L −/− mice.…”

Nuclear Factor I X Deficiency Causes Brain Malformation and Severe Skeletal Defects

“…Defects in reabsorption of CSF due to impaired function of ependymal cells or disturbed extracellular matrix can also lead to the development of hydrocephalus, as seen in transgenic mice overexpressing the cytokine transforming growth factor ␤1 (13). Misexpression of other factors such as matrix metalloproteinases and their specific inhibitors (tissue inhibitors of matrix metalloproteinases) have also been implicated in promoting hydrocephalus formation by altering the extracellular matrix environment (70). Since the Nfix gene is highly expressed in ependymal cells (Fig.…”

Genetics of human hydrocephalus

“…In the TGFB1 over-expression mouse model, the changing expressions of a remodeling protein - matrix metalloproteinase-9 (MMP-9) and its specific inhibitor- tissue inhibitor of metalloproteinases-1 (TIMP-1) were also found to be important factors in the spontaneous development of hydrocephalus by altering the ECM environment [119]. Furthermore, increased expression of cytokines such as TGFB1 might also reciprocally play an important role by disrupting the vascular ECM remodeling, promoting hemorrhages, and altering the re-absorption of CSF [120].…”