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Bone induction by TGF-beta family members
- Soluble, insoluble and geometric signals sculpt the architecture of mineralized tissues

Bone induction by TGF-β family members

Nature relies on common but limited molecular mechanisms tailored to direct the morphogenesis of specialized tissues and organs. The bone morphogenetic and osteogenic proteins family (BMPs/OPs), members of the transforming growth factor-β (TGF-β) supergene family, is indeed an elegant example of Nature’s parsimony in controlling multiple specialized functions or pleiotropy, deploying molecular isoforms with minor variations in amino acid motifs within highly conserved carboxy-terminal regions [2-6].

A striking and discriminatory prerogative of these morphogens, either naturally-derived or produced by DNA recombinant technologies, is their ability to induce de novo endochondral bone formation, i.e. via a cartilage phase, in heterotopic extraskeletal sites [2, 5, 7, 11–14] (Fig. 1A). The remarkable process of tissue morphogenesis and bone induction in postnatal life is a recapitulation of embryonic development whereby both embryonic development and tissue regeneration are regulated by a select few, highly conserved families of morphogens namely the BMPs/OPs family of the TGF-β superfamily [2, 5, 6, 12, 15, 16] (Fig. 1A).

BMPs/OPs are morphogens defined by Turing [17] as form generating substances, and when interacting with responding cells are capable of initiating the sequential cascade of events leading to pattern formation and the attainment of tissue form and function, i.e. morphogenesis [2, 6]. Thus these pleiotropic morphogens have potent and diverse effects on cell proliferation, differentiation, motility and matrix synthesis leading ultimately to cartilage and bone differentiation and regeneration [1, 2, 6, 12, 14].

The fact that a single recombinant human BMP/OP initiates bone formation by induction does not preclude interactions with other morphogens deployed synchronously, sequentially and synergistically during the cascade of bone formation by induction. Thus osteogenesis can occur via the combined action of several BMPs/OPs resident within the natural milieu of the extracellular matrix of bone [7, 10–12] (Fig. 1B).

The osteoinductive prerogative, originally solely ascribed to the BMPs/OPs, has now been extended to other TGF-β superfamily members, including decapentaplegic (DPP) and 60A gene products expressed early in Drosophila development [18], and growth and differentiation factor-5 [19]. Of particular interest is that in the species studied to date, the TGF-β isoforms in contrast to BMPs/OPs, initiate endochondral bone formation only in the primate [20–22] (Fig. 1C). In this animal model, the induction of bone by TGF-β isoforms is characterised by a marked site and tissue specificity [2, 10, 12, 20–23].

The presence of several molecular forms with osteogenic activity poses important questions about the biological significance of this apparent redundancy [10], indicating multiple interactions, or cross-talk between components of the signalling pathways initiating de novo bone formation and tissue morphogenesis in primate species.

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