The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1996/12/2311/ $5.00
The Journal of Experimental Medicine, Volume 184, Number 6, December 1, 1996 2311-2326

Articles

Basement Membrane and Repair of Injury to Peripheral Nerve: Defining a Potential Role for Macrophages, Matrix Metalloproteinases, and Tissue Inhibitor of Metalloproteinases-1

Monique La Fleur, Johnnie L. Underwood, Daniel A. Rappolee, and Zena Werb

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-{alpha} and TGF-β1 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-{alpha} 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-β1, TNF-{alpha}, and IL-1{alpha}. 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.

Address correspondence to Zena Werb, Department of Anatomy, LR208, Box 0750, University of California, San Francisco, CA 94143-0750. M. La Fleur's present address is Genentech, Inc., Research Bioassay, MS-50 South San Francisco, CA 94080. J.L. Underwood's present address is Department of Ophthalmology, University of California, San Francisco, CA 94143. D.A. Rappolee's present address is Department of Obstetrics/Gynecology, Northwestern University, Chicago, IL 60611.

This work was supported by a contract from the Office of Health and Environmental Research, U.S. Department of Energy (DE-AC03-76-SF01012), a grant from the National Institutes of Health Research Center in Oral Biology (DE10306), a Medical Research Council of Canada fellowship to M. La Fleur, and a National Research Service Award from the National Institute of Environmental Health Sciences (T32ES07106).

1Abbreviations used in this paper: APMA, 4-aminophenylmercuric acetate; ApoE, apolipoprotein E; BM, basement membrane; CM, conditioned medium; COL IV, type IV collagen; ECM, extracellular matrix; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; LH, lactalbumin hydrolysate; MMP, matrix metalloproteinase; NGF, nerve growth factor; RT, reverse transcriptase; TIMP, tissue inhibitor of metalloproteinases.


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