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
U. Ripamonti et al., 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, Journal of bone and mineral research, 12(10), 1997, pp. 1584-1595
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.