RECOMBINANT TRANSFORMING GROWTH-FACTOR-BETA-1 INDUCES ENDOCHONDRAL BONE IN THE BABOON AND SYNERGIZES WITH RECOMBINANT OSTEOGENIC PROTEIN-1 (BONE MORPHOGENETIC PROTEIN-7) TO INITIATE RAPID BONE-FORMATION

Several members of the bone morphogenetic protein (BMP) and transformi ng growth factor-beta (TGF-beta) families are molecular regulators of cartilage and bone regeneration, although their actual roles and combi ned interactions in skeletal repair are poorly understood. The presenc e of several molecular forms suggests multiple functions in vivo as we ll as synergistic interactions during both embryonic bone development and regeneration of cartilage and bone in postfetal life. Here we show for the first time that recombinant human transforming growth factor- beta 1 (TGF-beta 1) induces endochondral bone formation in extraskelet al sites of adult baboons. We also show that TGF-beta 1 and recombinan t human osteogenic protein-1 (OP-1, bone morphogenetic protein-7) syne rgize in inducing large ossicles in extraskeletal sites of the primate as early as 15 days after implantation. A single application of OP-1, in conjunction with an insoluble collagenous matrix as carrier (5, 25 , and 125 mu g/100 mg of carrier matrix) induced bone differentiation in the rectus abdominis of the baboon. This level of tissue induction was raised several-fold by the simultaneous addition of comparatively low doses of TGF-beta 1 (0.5, 1.5, and 5 mu g), which by itself induce s bone formation in the rectus abdominis at doses of 5 mu g/100 mg of carrier matrix. Combinations of OP-1 and TGF-beta 1 yielded a 2- to 3- fold increase in cross-sectional area of the newly generated ossicles, with markedly elevated key parameters of bone formation, and cortical ization of the newly formed bone by day 15, culminating in bone marrow generation by day 30. The tissue generated by the combined applicatio n of OP-1 and TGF-beta 1 showed distinct morphological differences whe n compared with OP-1-treated specimens, with large zones of endochondr al development and extensive bone marrow formation. At the doses teste d, synergy was optimal at a ratio of 1:20 by weight of TGF-beta 1 and OP-1, respectively. These results provide evidence for a novel functio n of TGF-beta 1 in the primate and the scientific basis for synergisti c molecular therapeutics for the rapid regeneration of cartilage and b one.