Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves

A single point mutation in peripheral myelin protein 22 (pmp22) of the Trembler-J (TrJ) mouse models the human peripheral neuropathy, Charcot-Marie-Tooth disease type 1 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 MMP-2 and MMP-9 proteins. In neuropathy nerves, elevated levels of MMP-2 and MMP-9 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 MMP-2- and MMP-9-expressing cells in TrJ nerves. Cell type-specific immunolabeling showed that infiltrating macrophages are a significant source of both MMP-2 and MMP-9. 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.