Metalloproteinases as mediators of tissue regeneration in the peripheral nerve: an important role for metalloproteinase-2

Background: Metalloproteinases (MMP) have been implicated to contribute to the harmful effects of inflammation in the peripheral nervous system by promoting cytotoxicity and breakdown of the blood-nerve-barrier. However, recent studies indicate that in a regenerative milieu, MMP-2 may also facilitate repair mechanisms by promoting axonal guidance and remodelling of the extracellular matrix. We discovered that MMP-2 was highly upregulated in naïve Schwann cell cultures and investigated therefore the expression of MMP-2 in cerebrospinal fluid (CSF) in patients with inflammatory neuropathies and an in-vitro model of myelination in the PNS.

Methods: MMP-2 expresssion was determined by ELISA-based MMP-2 activity assay in CSF from patients with inflammatory neuropathies. To study the effect of MMP-2 on myelination in vitro, dissociated embryonic dorsal root ganglia neurons and Schwann cells were maintained for approximately 30 days in culture until the Schwann cells had myelinated the sensory axons. Myelination was correlated with MMP-2 expression as determined by zymography. Further, chemical inhibitors of MMP-2 were added to the cultures to modulate MMP-2 activity.

Results: MMP-2 levels were significantly elevated in CSF from patients with inflammatory neuropathies. In vitro, during the process of myelination, MMP-2 was highly expressed but high levels of MMP-2 were not maintained in “steady state“ myelinated co-cultures. When inhibitors of MMP-2 were added during the early stages of the cell cultures, we found an incomplete and aberrant myelin formation. This negative effect of MMP-2 inhibition was not present in the later stages of the cell cultures, when the Schwann cells had completed myelin formation. MMP-14, which was expressed in axons activated the pro-form of MMP-2 in vitro.

Conclusion: Our findings suggest that MMP-2 is critically involved in the early process of myelination. MMP-14 may act as an axonal signal to activate MMP-2, which subsequently promotes the formation of myelin in the PNS. Our observations have implications for strategies of remyelination in patients with inflammatory neuropathies. The modulation of MMP activity as potential therapeutic approach must consider not only the known pathological effects of MMP's but also their beneficial effects on repair mechanisms in the peripheral nerve, including the process of (re)myelination.