Matrix metalloproteinase mediated degradation of basement membrane proteins in XXXX .

@entity16819 @entity1 @entity5108 @entity1476 @entity19 @entity16 @entity1897 @entity1495
A single point mutation in @entity16819 ( @entity16819 ) of the Trembler-J (TrJ) @entity19 models the @entity1 @entity1897 , @entity5108 A (CMT1A). An unexplored aspect of this disease is the gradual remodeling of the extracellular matrix in affected nerves. To elucidate the mechanism responsible for these changes, the levels of the extracellular matrix molecules laminin, collagen IV, and fibronectin were determined. In TrJ nerves, laminin is modestly increased while full-length forms of collagen IV and fibronectin are decreased. Matrix metalloproteinases (MMPs) are known to degrade multiple matrix molecules; therefore, nerves were assayed for @entity1476 and @entity1495 proteins. In @entity16 , elevated levels of @entity1476 and @entity1495 were detected on western blots, and gelatin zymography confirmed the up-regulation of gelatinalytic activity in affected samples. Immunostaining studies revealed an increase in the numbers of @entity1476 - and @entity1495 -expressing cells in TrJ nerves. Cell type-specific immunolabeling showed that infiltrating macrophages are a significant source of both @entity1476 and @entity1495 . Finally, the degradation of exogenous collagen IV by TrJ nerve lysates was prevented with a specific MMP inhibitor. Together these observations suggest that infiltration by MMP-expressing macrophages contributes to the remodeling of the TrJ nerve matrix.
