Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development

Abstract

The osteogenic molecular signals of the transforming growth factor-β (TGF-β ) superfamily, the bone morphogenetic/ osteogenic proteins (BMPs/OPs) and uniquely in primates the TGF-β isoforms per se , pleiotropic members of the TGF-β supergene family, induce de novo endochondral bone formation as a recapitulation of embryonic development. Naturally derived BMPs/OPs and gamma-irradiated human recombinant osteogenic protein-1 (hOP-1) delivered by allogeneic and xenogeneic insoluble collagenous matrices initiate de novo bone induction in heterotopic and orthotopic sites of the primate Papio ursinus , culminating in complete calvarial regeneration by day 90 and maintaining the regenerated structures by day 365. The induction of bone by hOP-1 in P. ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF-β superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis. The temporal and spatial expressions of TGF-β 1 mRNA indicate a specific temporal transcriptional window during which expression of TGF-β 1 is mandatory for successful and optimal osteogenesis. Highly purified naturally derived bovine BMPs/ OPs and hOP-1 delivered by human collagenous bone matrices and porous hydroxyapatite, respectively, induce bone formation in mandibular defects of human patients. By using healthy body sites as bioreactors it is possible to recapitulate embryonic developments by inducing selected biomaterials combined with recombinant proteins to transform into custom-made prefabricated bone grafts for human reconstruction. The osteogenic proteins of the TGF-β superfamily, BMPs/OPs and TGF-β s, the last endowed with the striking prerogative of inducing endochondral bone formation in primates only, are helping to engineer skeletal reconstruction in molecular terms.

Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization

“…(3) Recent evidence indicates that many of the bone extracellular matrix and signaling molecules, such as osteopontin, SPARC, fibronectin, collagens, and BMPs, are pleiotropic in nature and serve multiple functions ranging from pattern formation, osteoinduction, and osteoclastogenesis to the control of cell proliferation, cell differentiation, and cell adhesion. (4)(5)(6)(7)(8) In the present study, we focus on the role of a characteristically pleiotropic extracellular matrix molecule, the secretory calcium-binding phosphoprotein (SCPP) family member ameloblastin (AMBN).…”

Regenerative Frontiers in Craniofacial Reconstruction: Grand Challenges and Opportunities for the Mammalian Transforming Growth Factor-β Proteins

“…Due to constraints of space, the interested reader is encouraged to read the path of discoveries that have characterized the evolution of bone tissue engineering (Urist, 1994; Reddi, 2000; Ripamonti et al, 2006). …”

“…Through the centuries, several lucid investigators perceived that the extracellular matrix of bone must be a reservoir of differentiating and morphogenetic factors ultimately responsible for its pronounced healing potential (reviewed in Urist, 1968, 1994; Reddi, 2000; Ripamonti et al, 2006). …”

Genes and Molecular Pathways of the Osteogenic Process

“…As a rule, all the molecules acting in the TGF-β signaling pathway are extremely conserved across species during evolution (Miyazono, 2000). A fine regulation of the spatio-temporal expression and function of TGF-β pathway players occurs during embryonic development, leading to an astounding heterogeneity of cellular responses (Ripamonti et al, 2006). Signaling is initiated when binding of the ligand induces the assembly of a heteromeric complex of type I and type II serine/threonine kinase receptors (Cohen, 2006;Miyazono, 2000).…”