Bone Research Unit

Current projects

Controlled initiation of endochondral and membranous osteogenesis is a problem central to biologists, skeletal reconstructionist and biomaterial scientists alike.

A major advance in the understanding of bone formation has been the identification of an entirely new family of protein initiators - the bone morphogenetic proteins (BMPs) - also known as osteogenic proteins (Ops), that regulate cartilage and bone differentiation in vivo.

BMPs/OPs induce endochondral bone differentiation through a cascade of events, which include formation of cartilage and bone, hypertrophy and calcification of the cartilage, vascular invasion and differentiation of osteoblasts.

The BMPs/OPs (BMP -2-14, and osteogenic protein 1 and -2, OP-1 and OP-2) show sequence homologies with members of the transforming growth factor beta (TGF-beta) family, including developmentally critical regulatory genes such as decapentaplegic and 60A in Drosophila, vegetal (Vg-1) in Xenopus, and in activins and inhibins. (are these meant to be hyphens? Please advise)

The striking evolutionary conservation of the BMP/OP genes indicates that they are critical in the normal development and functioning of animals. Moreover, the presence of multiple forms of BMPs/OPs raises an important question about the biological relevance of this apparent redundancy.

In addition to post-fetal chondrogenesis and osteogenesis, the BMPs/OPs play multiple roles in skeletogenesis (including the development of craniofacial and dental tissues) and in embryonic development and organogenesis of parenchymatous organs, including the kidney.

We now understand that nature relies on common (and few) molecular mechanisms tailored to provide the emergence of specialised tissues and organs. The BMP/OP super-family is indeed an elegant example of natural parsimony as multiple, specialised functions are programmed, deploying molecular isoforms with minor variations in amino acid motifs, within highly conserved carboxy terminal regions.

The Research Unit hypothesises that the capacity of mammalian BMPs/OPs to initiate a programmed cellular cascade, resulting in the induction of cartilage and bone, is a functionally conserved process used in embryonic development and recapitulated in post-fetal osteogenesis, which can be exploited for the therapeutic initiation of bone formation.

Thus, BMPs/OPs are the common molecular initiators deployed for embryonic development and induction of bone formation and regeneration in postnatal osteogenesis. And this finding is helping us to engineer skeletal regeneration in molecular terms.

Current and future research projects are divided into four broad areas of investigation:

• BMPs/OPs: Molecular therapeutics for tissue morphogenesis and regeneration;
• Inductive biomaterials for tissue engineering and cost-effective treatment of skeletal defects;
• Osteopenic primate model and systemic administration of recombinant morphogens;
• Paleopathology of hominid gnathic remains.

Our previous work has demonstrated the efficacy and safety of naturally sourced BMP/OPs for bone regeneration in adult baboons. Highly purified BMPs/OPs can be used for the architectural reconstruction of the bone-bone marrow organ in the adult primate.

Expression cloning of the BMP/OP family members has now set the stage for novel therapeutic approaches to correct congenital and acquired craniofacial and orthopaedic conditions.

This will require the use of a single (or combined) recombinant human BMP/OP delivered by appropriate carriers. This prediction needs to be evaluated experimentally, however, on non-human primates.

Our work on rh BMPs/OPs has shown that a single recombinant factor (hOP-1, also known as BMP-7) is capable of initiating bone differentiation in adult primates.