title: Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells.
abstract: After peripheral nerve injury, Schwann cells (SCs) vigorously divide to survive and produce a sufficient number of cells to accompany regenerating axons. Matrix metalloproteinases (MMPs) have emerged as modulators of SC signaling and mitosis. Using a 5-bromo-2-deoxyuridine (BrdU) incorporation assay, we previously found that a broad-spectrum MMP inhibitor (MMPi), GM6001 (or ilomastat), enhanced division of cultured primary SCs. Here, we tested the hypothesis that the ability of MMPi to stimulate SC mitosis may advance nerve regeneration in vivo. GM6001 administration immediately after rat sciatic nerve crush and daily thereafter produced increased nerve regeneration as determined by nerve pinch test and growth-associated protein 43 expression. The MMPi promoted endoneurial BrdU incorporation relative to vehicle control. The dividing cells were mainly SCs and were associated with growth-associated protein 43-positive regenerating axons. After MMP inhibition, myelin basic protein mRNA expression (determined by Taqman real-time quantitative polymerase chain reaction) and active mitosis of myelin-forming SCs were reduced, indicating that MMPs may suppress their dedifferentiation preceding mitosis. Intrasciatic injection of mitomycin,the inhibitor of SC mitosis, suppressed nerve regrowth, which was reversed by MMPi, suggesting that its effect on axonal growth promotion depends on its promitogenic action in SCs. These studies establish novel roles for MMPs in peripheral nerve repair via control of SC mitosis, differentiation, and myelin protein mRNA expression.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, California 92093-0629, USA.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.forename: Youngsoon
authors.initials: Y
authors.lastname: Kim
authors.forename: Sharmila
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Igor
authors.initials: I
authors.lastname: Shubayev
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dolkas
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Shubayev
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D008938:Mitosis / Q000187:drug effects*; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D010147:Pain Measurement / Q000379:methods; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects*; D020426:Sciatic Neuropathy / Q000150:complications
chemical_list: D004151:Dipeptides; D019922:GAP-43 Protein; D061965:Matrix Metalloproteinase Inhibitors; D004676:Myelin Basic Protein; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; D001973:Bromodeoxyuridine
references.citation: Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4747-53
references.pmid: 16303975
references.citation: Growth Factors. 2006 Jun;24(2):121-36
references.pmid: 16801132
references.citation: J Neurosci. 2002 Sep 1;22(17):7526-35
references.pmid: 12196576
references.citation: J Neurosci. 2007 Jul 25;27(30):7911-20
references.pmid: 17652582
references.citation: J Neurosci. 2008 Sep 17;28(38):9330-41
references.pmid: 18799667
references.citation: Neuroscience. 2002;115(1):321-9
references.pmid: 12401344
references.citation: Biochem Pharmacol. 1996 Jul 12;52(1):105-11
references.pmid: 8678893
references.citation: Stem Cells. 1997;15(3):180-9
references.pmid: 9170209
references.citation: J Peripher Nerv Syst. 2002 Mar;7(1):28-36
references.pmid: 11939349
references.citation: Mol Cell Neurosci. 2008 Dec;39(4):619-27
references.pmid: 18817874
references.citation: Proc Natl Acad Sci U S A. 1988 Mar;85(5):1701-5
references.pmid: 3422757
references.citation: J Neurosci Res. 2010 Feb 1;88(2):360-8
references.pmid: 19746434
references.citation: Brain Res. 1977 Sep 2;132(3):443-53
references.pmid: 199316
references.citation: Annu Rev Neurosci. 1990;13:43-60
references.pmid: 2183684
references.citation: J Neurosci. 2006 Feb 22;26(8):2207-14
references.pmid: 16495447
references.citation: Exp Neurol. 2008 Jul;212(1):189-200
references.pmid: 18501894
references.citation: Clin Neuropharmacol. 2004 Nov-Dec;27(6):293-8
references.pmid: 15613934
references.citation: Glia. 2009 Sep;57(12):1316-25
references.pmid: 19229995
references.citation: J Neuropathol Exp Neurol. 2005 Jul;64(7):613-22
references.pmid: 16042313
references.citation: Neuron Glia Biol. 2006 May;2(2):139-47
references.pmid: 18634586
references.citation: J Neurosci Res. 1990 Jul;26(3):317-26
references.pmid: 1697906
references.citation: BMC Neurosci. 2008 Sep 09;9:83
references.pmid: 18778487
references.citation: J Neurosci. 2005 Apr 6;25(14):3701-11
references.pmid: 15814801
references.citation: Brain Res. 1985 Aug 19;341(1):16-25
references.pmid: 3929995
references.citation: J Neurosci. 2006 Sep 27;26(39):9841-50
references.pmid: 17005848
references.citation: Neuroscience. 2002;113(2):273-87
references.pmid: 12127085
references.citation: Neurosci Lett. 1995 Dec 15;201(3):223-6
references.pmid: 8786845
references.citation: J Neurochem. 1969 Feb;16(2):235-48
references.pmid: 5795937
references.citation: Sci STKE. 2006 Mar 07;2006(325):pe11
references.pmid: 16522871
references.citation: Glia. 2009 Apr 1;57(5):479-89
references.pmid: 18814268
references.citation: J Exp Med. 1996 Dec 1;184(6):2311-26
references.pmid: 8976186
references.citation: J Neuroimmunol. 2008 Jan;193(1-2):140-8
references.pmid: 18063113
references.citation: J Immunol. 2005 Feb 15;174(4):2288-96
references.pmid: 15699164
references.citation: J Neurosci. 2005 Feb 2;25(5):1179-87
references.pmid: 15689554
references.citation: J Biol Chem. 2002 Dec 27;277(52):50326-32
references.pmid: 12384502
references.citation: Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
references.pmid: 17318226
references.citation: Nat Rev Neurosci. 2005 Sep;6(9):671-82
references.pmid: 16136171
references.citation: J Neurosci Res. 2003 Nov 1;74(3):417-29
references.pmid: 14598318
references.citation: J Neurosci. 2009 Aug 12;29(32):9967-76
references.pmid: 19675231
references.citation: Brain Behav Immun. 2007 Jul;21(5):561-8
references.pmid: 17189680
references.citation: J Neurocytol. 1989 Apr;18(2):185-92
references.pmid: 2543799
references.citation: J Neurosci. 2008 Nov 5;28(45):11571-82
references.pmid: 18987193
references.citation: J Clin Invest. 1994 Dec;94(6):2177-82
references.pmid: 7989572
references.citation: Mol Cell Neurosci. 2006 Mar;31(3):407-15
references.pmid: 16297636
references.citation: J Neurosci Res. 1993 Nov 1;36(4):432-40
references.pmid: 7505841
references.citation: J Neurosci. 2002 Dec 1;22(23):10408-15
references.pmid: 12451140
references.citation: Brain Res. 1988 Sep;464(2):133-41
references.pmid: 2464407
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: J Neurosci. 1998 Jul 15;18(14):5203-11
references.pmid: 9651203
references.citation: J Cell Biol. 1992 Jan;116(1):177-85
references.pmid: 1730742
references.citation: J Neurochem. 2007 Aug;102(3):900-12
references.pmid: 17561941
references.citation: J Neuropathol Exp Neurol. 2001 Jan;60(1):85-93
references.pmid: 11202178
references.citation: Nat Neurosci. 2007 Nov;10(11):1361-8
references.pmid: 17965656
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Neuroscience. 2008 Apr 9;152(4):877-87
references.pmid: 18358630
references.citation: Nature. 1974 Nov 22;252(5481):303-5
references.pmid: 4431449
references.citation: J Peripher Nerv Syst. 2002 Mar;7(1):13-27
references.pmid: 11939348
references.citation: Neurobiol Dis. 2007 Mar;25(3):526-35
references.pmid: 17188498
references.citation: J Physiol. 1943 Mar 25;101(4):489-518
references.pmid: 16991581