Absence of mechanical allodynia and Aβ‐fiber sprouting after sciatic nerve injury in mice lacking membrane‐type 5 matrix metalloproteinase

Abstract

Matrix metalloproteinases (MMPs) are a family of endopeptidases that degrade extracellular matrix components. Membrane-type 5 MMP (MT5-MMP/MMP-24) was identi¢ed as neuron-speci¢c, and is believed to contribute to neuronal circuit formation and plasticity. To elucidate its function in vivo, we have generated mice lacking MT5-MMP by gene targeting. MT5-MMP-de¢cient mice were born without obvious morphological abnormalities. No apparent histological defects were observed in the nervous system either. However, MT5-MMP-de¢cient mice did not develop neuropathic pain with mechanical allodynia after sciatic nerve injury, though responses to acute noxious stimuli were normal. Neuropathic pain induced by peripheral nerve lesions is known to accompany structural reorganization of the nervous system. Intraneural injection of cholera toxin B subunit, a transganglionic tracer, into the injured sciatic nerve of wild-type mice revealed that the myelinated AL L¢ber primary a¡erents sprouted from laminae III^VI of the dorsal horn of the spinal cord and invaded lamina II. However, no such sprouting and invasion of AL L-¢bers were observed in MT5-MMP-de¢cient mice. These ¢ndings suggest that MT5-MMP is essential for the development of mechanical allodynia and plays an important role in neuronal plasticity in this mouse model.

Cytokine regulation of MMP-9 in peripheral glia: Implications for pathological processes and pain in injured nerve

“…To date, two other studies directly assessed the effect of MMP inhibition on neuropathic pain. MT5-MMP gene deletion virtually ablated mechanical allodynia associated with partial sciatic nerve ligation (Komori et al, 2004), and synthetic inhibitor TAPI significantly reduced thermal hyperalgesia and mechanical allodynia after chronic constriction injury in mice (Sommer et al, 1997). TAPI inhibits TNF-α activation by chelating TNF-α converting enzyme (TACE) and, at higher doses, MMP-9 and other MMPs.…”

Membrane Localization of Membrane Type 5 Matrix Metalloproteinase by AMPA Receptor Binding Protein and Cleavage of Cadherins

“…MT5-MMP is a membrane-bound, brain-specific matrix metalloproteinase that participates in axodendritic development and remodeling after nerve injury (Hayashita-Kinoh et al, 2001;SekineAizawa et al, 2001;Komori et al, 2004). It is expressed in brain regions active in plasticity, including the hippocampus and cerebellum, and it may also degrade inhibitory extracellular matrix molecules such as proteoglycans during axonal elongation and synaptogenesis (Hayashita-Kinoh et al, 2001).…”

“…MT5-MMP may promote axon and dendrite extension (Hayashita-Kinoh et al, 2001;Sekine-Aizawa et al, 2001) and structural remodeling after nerve injury (Komori et al, 2004). However, the role of MT5-MMP in mature neurons, specifically in synaptic plasticity, is unknown.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…MMP-24 is expressed in brain tissue after the development and colocalization with senile plaques in Alzheimer brain indicates possible roles in neuronal remodeling naturally occurring in adulthood and in regulating pathophysiological processes associated with advanced age (Sekine-Aizawa et al, 2001). MT5-MMP expressed in neurons may play a role in axonal growth that contributes to the regulation of neural network formation (Hayashita-Kinoh et al, 2001) and may promote structural remodeling after nerve injury (Komori et al, 2004). 7.5.3.2.…”