Antisense inhibition of connective tissue growth factor (CTGF/CCN2) mRNA limits hypertrophic scarring without affecting wound healing in vivo.
Augmented expression of connective tissue growth factor (CTGF/CCN2) is observed in healing wounds and in a variety of fibrotic disorders. It appears to enhance many of the effects of transforming growth factor-beta and has been shown to have independent fibrogenic functions. Despite these observations, its importance to dermal wound healing and the transition from wound to scar remains poorly defined. In this study, we use established rabbit models to evaluate the roles of CTGF in dermal wound healing and hypertrophic scarring. We show that CTGF mRNA demonstrates persistent up-regulation in hypertrophic scars. Treatment of wounds with antisense oligonucleotides to CTGF has no measurable effect on early wound closure. However, antisense therapy significantly limits subsequent hypertrophic scarring. Inhibition of CTGF is associated with a marked reduction in the number of myofibroblasts in scars and decreased transcription of TIMP-1 and types I and III collagen. These findings confirm CTGF to be a key mediator of hypertrophic scarring in this model. Its effect on myofibroblasts in this setting suggests a mechanism whereby it plays this role. Its limited participation in early healing implies that it may be a useful and specific target for modulating hypertrophic scarring following injury.
Sisco
Mark
M
Division of Plastic and Reconstructive Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, 675 N. St. Clair, Chicago, IL 60611, USA.
Kryger
Zol B
ZB
O'Shaughnessy
Kristina D
KD
Kim
Peter S
PS
Schultz
Greg S
GS
Ding
Xian-Zhong
XZ
Roy
Nakshatra K
NK
Dean
Nicholas M
NM
Mustoe
Thomas A
TA
D000818:Animals; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy*; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011817:Rabbits; D014945:Wound Healing / Q000187:drug effects*
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor