Transforming growth factor-β3 in primate tissue induction: Heterotopic osteogenesis, periodontal cementogenesis and the limits of clinical translation; A personal historical perspective.

It has been demonstrated that naturally derived osteogenic proteins extracted and purified from allogeneic bone matrices, reconstituted and implanted in the rectus abdominis muscle of recipient non-human primates of the species Papio ursinus, induce bone as a recapitulation of embryonic development. There is the induction of cartilage anlagen, angiogenesis, and vascular invasion, chondrolysis with the induction of osteoblast differentiation and bone matrix deposition. Recombinant human osteogenic protein-1 (hOP-1) also induces large ossicles in the rectus abdominis muscle of Papio ursinus. Our laboratories have also shown the extraordinary induction of bone formation by the three mammalian transforming growth factor-β isoforms (TGF-βs) with recombinant hTGF-β3 being the most powerful recombinant morphogen so far evaluated in Papio ursinus. Despite the induction of heterotopic bone by hOP-1, and particularly by hTGF-β3, translation in clinical contexts to regenerate mandibular defects is disappointing, with the induction of clinically insufficient bone volumes. Recombinant hTGF-β3 is endowed with most significant multifaceted pleiotropic activities spanning from the substantial induction of heterotopic endochondral bone formation, periodontal organogenesis with the induction of vascularized cementogenesis, to tissue transfiguration of neoplastic masses in vivo. This perspective reviews the pleiotropic activities of hTGF-β3 and proposes that the induction of bone formation by the osteogenic proteins of the TGF-β superfamily in heterotopic sites of the non-human primate Papio ursinus is evolutionarily redundant and thus unsuitable to translate the substantial induction of heterotopic endochondral bone in clinical contexts.