Abstract
Predictable bone induction in clinical contexts requires information on the expression and cross regulation of gene products of the transforming growth factor-beta (TGF-beta) superfamily elicited by single applications of each recombinant human bone morphogenetic/osteogenic proteins (BMPs/OPs). Using the calvarium and the rectus abdominis muscle of adult baboons Papio ursinus as a model for tissue induction and morphogenesis, this study investigated the induction of bone morphogenesis by gamma-irradiated hOP-1 delivered by gamma-irradiated bovine insoluble collagenous bone matrix, the hOP-1 osteogenic device, for bone induction in heterotopic and orthotopic sites of the primate Papio ursinus and the expression patterns of OP-1, collagen type IV, BMP-3 and TGFbeta1mRNAs elicited by increasing single applications of doses of the hOP-1 osteogenic devices (0.1, 0.5 and 2.5 mg hOP-1/g of matrix) applied heterotopically in the rectus abdominis muscle and orthotopically in 48 calvarial defects of 12 adult baboons. Histology and histomorphometry on serial undecalcified sections prepared from the specimens harvested on day 15, 30 and 90 showed that all the doses of the hOP-1 osteogenic device induced bone formation culminating in complete calvarial regeneration by day 90. Type IV collagen mRNA expression, a marker of angiogenesis, was strongly expressed in both heterotopic and orthotopic tissues. High levels of expression of OP-1 mRNA demonstrated autoinduction of OP-1 mRNAs. Expression levels of BMP-3 mRNA varied from tissues induced in heterotopic vs. orthotopic sites with high expression in rapidly forming heterotopic ossicles together with high expression of type IV collagen mRNA. The temporal and spatial expressions of TGF-beta1 mRNAindicate a specific temporal transcriptional window during which expression of TGF-beta1 is mandatory for successful and optimal osteogenesis. The induction of bone by hOP-1 in Papio ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF-beta superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis.