Effect of adenoviral mediated overexpression of fibromodulin on human dermal fibroblasts and scar formation in full-thickness incisional wounds.
Fibromodulin, a member of the small leucine-rich proteoglycan family, has been recently suggested as a biologically significant mediator of fetal scarless repair. To assess the role of fibromodulin in the tissue remodeling, we constructed an adenoviral vector expressing human fibromodulin cDNA. We evaluated the effect of adenovirus-mediated overexpression of fibromodulin in vitro on transforming growth factors and metalloproteinases in fibroblasts and in vivo on full-thickness incisional wounds in a rabbit model. In vitro, we found that Ad-Fibromodulin induced a decrease of expression of TGF-beta(1) and TGF-beta(2) precursor proteins, but an increase in expression of TGF-beta(3) precursor protein and TGF-beta type II receptor. In addition, fibromodulin overexpression resulted in decreased MMP-1 and MMP-3 protein secretion but increased MMP-2, TIMP-1, and TIMP-2 secretion, whereas MMP-9 and MMP-13 were not influenced by fibromodulin overexpression. In vivo evaluation by histopathology and tensile strength demonstrated that Ad-Fibromodulin administration could ameliorate wound healing in incisional wounds. In conclusion, although the mechanism of scar formation in adult wounds remains incompletely understood, we found that fibromodulin overexpression improves wound healing in vivo, suggesting that fibromodulin may be a key mediator in reduced scarring.
Stoff
Alexander
A
Division of Human Gene Therapy, Gene Therapy Center, University of Alabama at Birmingham, 901 19th Street South, BMR2 502, Birmingham, AL, 35294-2172, USA.
Rivera
Angel A
AA
Mathis
J Michael
JM
Moore
Steven T
ST
Banerjee
N S
NS
Everts
Maaike
M
Espinosa-de-los-Monteros
Antonio
A
Novak
Zdenek
Z
Vasconez
Luis O
LO
Broker
Thomas R
TR
Richter
Dirk F
DF
Feldman
Dale
D
Siegal
Gene P
GP
Stoff-Khalili
Mariam A
MA
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002921:Cicatrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D062109:Dermatologic Surgical Procedures; D020405:Dermis / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D000071235:Fibromodulin; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D011817:Rabbits; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013718:Tensile Strength; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014162:Transfection; D015291:Transforming Growth Factors / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics
D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D019714:Tissue Inhibitor of Metalloproteinases; D000071235:Fibromodulin; D015291:Transforming Growth Factors; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053505:Matrix Metalloproteinases, Secreted