TGF-BETA(1) INDUCES BONE CLOSURE OF SKULL DEFECTS - TEMPORAL DYNAMICSOF BONE-FORMATION IN DEFECTS EXPOSED TO RHTGF-BETA(1)

The temporal dynamics of bone repair in a skull defect in rabbits was examined to characterize the in vivo cellular events occurring followi ng a single local application of recombinant human TGF-beta1 (rhTGF-be ta1). Rabbits received vehicle or 0.4, 1, 2, or 5 mug rhTGF-beta1 appl ied to 12 mm defects at the time of surgery. The defect sites were sub sequently evaluated by radiography and qualitative and quantitative hi stology at time points ranging from 1 to 180 days. Based on radiograph ic assessment, the defect area decreased rapidly in a dose-dependent m anner through 35 days after surgery in the rhTGF-beta1-treated groups. Minimal closure occurred in sites administered vehicle control at all time points examined. Sites treated with rhTGF-beta1 were characteriz ed histologically by an increase in parameters of active bone formatio n through 49 days, including percentage osteoid surface, percentage os teoblast/total surface, and an increase in the trabecular bone volume. Bone resorption parameters were increased at 16 and 49 days with hist ologic evidence of remodeling from woven to lamellar bone. By 70 days, no differences were observed among the groups for parameters of eithe r bone formation or resorption. Bone formation rate was not altered wi th rhTGF-beta1 treatment at any time point. These results indicate tha t exogenously applied rhTGF-beta1 stimulated the recruitment and proli feration of osteoblasts at the defect site, resulting in a rapid depos ition of bony matrix, with normal remodeling processes occurring there after. This study supports the hypothesis that TGF-beta1 is a potent o steoinductive growth factor in vivo and may have potential application as a therapeutic aid to nonhealing bony defects.