Decorin antisense gene therapy improves functional healing of early rabbitligament scar with enhanced collagen fibrillogenesis in vivo

Injured ligaments heal with scar tissue, which has mechanical properties in ferior to those of normal ligament, potentially resulting in re-injury, joi nt instability, and subsequent degenerative arthritis. In ligament scars, n ormal large-diameter collagen fibrils have been shown to be replaced by a h omogenous population of small collagen fibrils. Because collagen is a major tensile load-bearing matrix element and because the proteoglycan decorin i s known to inhibit collagen fibrillogenesis, we hypothesized that the resto ration of larger collagen fibrils in a rabbit ligament scar, by down-regula ting the proteoglycan decorin, would improve the mechanical properties of s car. In contrast to sense and injection-treated controls, in vivo treatment of injured ligament by antisense decorin oligodeoxynucleotides led to an i ncreased development of larger collagen fibrils in early scar and a signifi cant improvement in both scar failure strength (83-85% improvement at 6 wee ks; 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 processe s with gene therapy. These findings not only suggest the potential use of t his 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 be tter understand specific structure-function relationships in scars.