Decorin antisense gene therapy improves functional healing of early rabbit ligament scar with enhanced collagen fibrillogenesis in vivo.
Injured ligaments heal with scar tissue, which has mechanical properties inferior to those of normal ligament, potentially resulting in re-injury, joint instability, and subsequent degenerative arthritis. In ligament scars, normal large-diameter collagen fibrils have been shown to be replaced by a homogenous population of small collagen fibrils. Because collagen is a major tensile load-bearing matrix element and because the proteoglycan decorin is known to inhibit collagen fibrillogenesis, we hypothesized that the restoration of larger collagen fibrils in a rabbit ligament scar, by down-regulating the proteoglycan decorin, would improve the mechanical properties of scar. In contrast to sense and injection-treated controls, in vivo treatment of injured ligament by antisense decorin oligodeoxynucleotides led to an increased development of larger collagen fibrils in early scar and a significant improvement in both scar failure strength (83-85% improvement at 6 weeks; p < 0.01) and scar creep elongation (33-48% less irrecoverable creep; p < 0.03) under loading. This is the first report that in vivo manipulation of collagen fibrillogenesis improves tissue function during repair processes with gene therapy. These findings not only suggest the potential use of this type of approach to improve the healing of various soft tissues (skin, ligament, tendon, and so on) but also support the use of such methods to better understand specific structure-function relationships in scars.
Nakamura
N
N
McCaig Centre for Joint Injury and Arthritis Research, University of Calgary, Alberta, Canada.
Hart
D A
DA
Boorman
R S
RS
Kaneda
Y
Y
Shrive
N G
NG
Marchuk
L L
LL
Shino
K
K
Ochi
T
T
Frank
C B
CB
D000818:Animals; D001696:Biomechanical Phenomena; D002921:Cicatrix / Q000628:therapy*; D003094:Collagen / Q000096:biosynthesis; D016373:DNA, Antisense / Q000494:pharmacology; D058575:Decorin; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D017888:Medial Collateral Ligament, Knee / Q000293:injuries* / Q000502:physiology; D008854:Microscopy, Electron; D011509:Proteoglycans / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013314:Stress, Mechanical; D014945:Wound Healing / Q000235:genetics*
D016373:DNA, Antisense; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D003094:Collagen