Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degenera- tion and regeneration. It is not known how Schwann cell–derived basement membrane is pre- served 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 mem- brane 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- a and TGF- B 1 mRNAs, known modulators of TIMP-1 ex- pression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF- a mRNAs were localized to infiltrating mac- rophages 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- B 1, TNF- a , and IL-1 a . These results show that TIMP-1 may protect basement membrane from uncontrolled degrada- tion after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.
Obstetrics and Gynecology
La Fleur, Monique; Underwood, Johnnie L.; Rappolee, Daniel A.; and Werb, Zena, "Basement Membrane and Repair of Injury to Peripheral Nerve: Deﬁning a Potential Role for Macrophages, Matrix Metalloproteinases, and Tissue Inhibitor of Metalloproteinases-1" (1996). Department of Obstetrics and Gynecology Research Publications. Paper 6.