Global morphogenesis regulating tissue architecture and organogenesis

This perspective article proposes that the induction of bone by recombinant human bone morphogenetic proteins (hBMPs), and by the recombinant human transforming growth factor-β₃ (hTGF-β₃), the latter only in primates, recapitulates embryonic development, whereby large ossicles de novo form in heterotopic intramuscular sites, where several responding cells are available with marked vascular invasion. The induction of bone initiates with the induction of cartilage' anlages recapitulating development. Selected recombinant hBMPs, hBMP-2 and hOP-1 (hBMP-7) on the other hand, fail to induce significant osteoinduction in orthotopic intraskeletal sites in clinical contexts. This review proposes that the failure of significant clinical bone formation in orthotopic sites is because implantation of hBMP-2 and hOP-1, as well as hTGF-β₃ in human mandibular sites, does not proceed via recapitulation of embryonic development, ultimately failing the clinical translation of the "bone induction principle". Biologically, a prerogative of the osteogenic proteins of the TGF-β super family, is the heterotopic induction of bone that initiates via recapitulation of embryonic bone development. Delivery of recombinant hBMP-2 and/or hOP-1 into human bony defects fails because the induction of bone is possible only via embryonic development, which does not occur in orthotopic sites, with limited responding cells and vascular supply. The initiation and assembly of the bone/bone-marrow organ follow a multistep molecular and cellular cascades that ultimately morphogenize the assembly of skeletogenesis masterminding ambulation, body erection, masticatory functions, copulation and the preservation of vital organs and tissues such as the marrow and the cerebral hemispheres. Embryologically, bone forms either via mesenchymal osteogenesis or via endochondral osteogenesis. The former route prevalently sculpts the craniomandibulofacial bones by inducing aggregation of targeted mesenchymal cells to condensate in the primordia of the craniofacial skeleton. A critical step is the condensation of mesenchymal cells that forms around vessels, as the vessels guide the formation of bone. Endochondral osteogenesis initiates by firstly constructing cartilage' anlages that developing bone uses as struts to growth and differentiate. The cartilage anlage is an extraordinary conduit that sets into motion molecular and cellular cell-to-cell, cell-to-receptors cross-talking to initiate angiogenesis and capillary invasion within the hypertrophic cartilage, chondrolysis that initiate osteoblastic cellular differentiation and the deposition of bone, osteoid synthesis, bone marrow development and the induction of a complete mineralized bone-bone marrow organ. The assembled constructs are storage of critical ions, several structural proteins such as osteonectins and fibronectins, biological markers of osteoblast' secretion and activity, such as osteocalcin, together with an array of extraordinary morphogen initiators that de novo set into motion the molecular and cellular cascades inducing bone in heterotopic sites recapitulating embryonic development. In evolutionary molecular biology contexts however, the pleiotropic activities of both proteins' family and the induction of bone formation in heterotopic sites are developmental, and thus not suitable to induce bone when recombinant morphogens are singly implanted in orthotopic skeletal defects, the latter lacking the developmental biological platform.