Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration.
We studied the role of the matrix metalloproteinase gelatinase B (gelB; MMP-9) in epithelial regeneration using the gelB-deficient mouse. We report the novel finding that, in contrast to other MMPs expressed at the front of the advancing epithelial sheet in wounds of cornea, skin, or trachea, gelB acts to inhibit the rate of wound closure. We determined this to be due to control of cell replication, a novel capacity for MMPs not previously described. We also found that gelB delays the inflammatory response. Acceleration of these processes in gelB-deficient mice is correlated with a delay in signal transduction through Smad2, a transcription factor that inhibits cell proliferation, and in accumulation of epithelial-associated interleukin-1alpha, a cytokine that inhibits Smad2 signaling and promotes the inflammatory response. GelB-deficient mice also reveal defects in remodeling of extracellular matrix at the epithelial basement membrane zone, in particular, failure to effectively remove the fibrin(ogen) provisional matrix. We conclude that gelB coordinates and effects multiple events involved in the process of epithelial regeneration.
Mohan
Royce
R
New England Eye Center, Tufts University School of Medicine, and the Tufts Center for Vision Research, Boston, Massachusetts 02111, USA.
Chintala
Shravan K
SK
Jung
Jae Chang
JC
Villar
Winston V L
WV
McCabe
Frank
F
Russo
Laoti A
LA
Lee
Yunhee
Y
McCarthy
Brendan E
BE
Wollenberg
Kurt R
KR
Jester
James V
JV
Wang
Min
M
Welgus
Howard G
HG
Shipley
J Michael
JM
Senior
Robert M
RM
Fini
M Elizabeth
ME
D000818:Animals; D001485:Basement Membrane; D003315:Cornea / Q000166:cytology* / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012038:Regeneration; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D014945:Wound Healing
D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D020780:Matrix Metalloproteinase 9