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By
From the Department of Anatomy and Laboratory of Radiobiology and Environmental Health,
University of California, San Francisco, California 94143-0750
Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell-derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in
axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9),
stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in
excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of
nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush)
after injury, induction of TNF-
and TGF-
1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days
after injury, TIMP-1, gelatinase B, and TNF- mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1
and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with
medium conditioned by macrophages or containing the cytokines TGF-1, TNF-, and IL-1.
These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation
of TIMP-1 levels during nerve repair.
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