The Induction of Bone Formation by the recombinant human transforming growth Factor-β3 : From preclinical studies in Papio ursinus to translational research in Homo sapiens

Abstract

Skeletal bone defects of the axial or the craniomaxillofacial skeletons still present formidable challenges to skeletal reconstructionists, tissue biologists and modern medicine. In systematic research experiments in the Chacma baboon Papio ursinus our laboratories have shown the previously unreported osteoinductive activity of the three mammalian transforming growth factor-β (TGF-β) isoforms. This review discusses the induction of bone formation by the mammalian TGF-βs with particular reference to the substantial and rapid induction of bone by the recombinant hTGF-β3 from the laboratory benches, to pre-clinical studies in heterotopic and orthotopic mandibular sites of Papio ursinus to clinical translation in human patients. Design and MethodsA series of systematic research experiments in Papio ursinus using the hTGF-β3 together with earlier experiments using the -β1 and β2 isoforms are reviewed and re-analyzed molecularly nd morphologically to provide the basic research data for the reported clinical translation in human patients. Results The three mammalian hTGF-β isoforms and notably hTGF-β3 induce rapid and substantial induction of heterotopic bone in intramuscular sites of Papio ursinus. Relatively low doses of hTGF-β1or hTGF-β3 in binary application with hBMP-7 synergize to induce massive corticalized ossicles in the rectus abdominis muscle. In orthotopic mandibular sites, 125 and250 µg doses of hTGF-β3 induce bone formation across large mandibular defects in Papio ursinus with corticalized buccal and lingual plates by day 30, with modeling and maintenance of corticalized bone by 9 to 12 months after implantation of the 250 µg dose in 3 cm mandibular defects Papio ursinus. Discussion hTGF-β3 significantly up-regulates RUNX-2 and Osteocalcin expression on day 15 controlling the differentiation of progenitor stem cells into the osteoblastic lineage. The induction of bone by the hTGF-β3 is via the bone morphogenetic proteins pathway; hTGF-β3 controls theinduction of bone by regulating the expression of BMPs gene and gene products via Noggin expression, eliciting bone induction by up-regulating exogenous BMPs.