Bone regeneration

In the past few years, the Bone Research Laboratory, a Research Unit of the South African Medical Research Council and the University of the Witwatersrand, Johannesburg, has made great strides to further understand the mechanisms of bone repair and regeneration.

 

Bone has a remarkable potential to repair itself and this was well known since antiquity; indeed Hippocrates, the father of medicine, noted that bone heals without scarring. However broken bones and loss of bone substance, also called bony defects throughout the skeleton, including the craniofacial skeleton, do not heal properly. And this is where greater scientific and practical interventions are needed.

Over decades of interest in bone repair and regeneration, no single concept has captured the imagination to a greater degree than the phenomenon of bone formation.

Many scientists around the world studied this phenomenon and few excelled; Gustav Levander last century showed that fragments of bone treated with alcohol would induce new bone formation when implanted into muscle of a recipient animal where there is no bone.

Later, Marshall Urist unequivocally demonstrated that implantation of demineralized bone matrix into muscle of rodents would induce new bone formation, a phenomenon he has named “bone: formation by autoinduction”, in his classic paper published Science in 1965.

Urist during his prodigious scientific career and output later postulated that the remarkable capacity of bone to mend itself was due to a bone morphogenetic protein complex within the bone matrix.

Many scientists throughout the world devoted themselves to isolate and identify this hypothesized and elusive bone morphogenetic protein complex.

Later, different scientists independently isolated the bone morphogenetic proteins (in short BMPs) from the bone matrix. BMPs are capable of initiating the cascade of bone differentiation by induction even when implanted in non-bony muscle sites.

Until 1997, BMPs were theorized to be the only proteins capable of inducing bone formation. That is until the Bone Research Laboratory, headed by Professor Ripamonti of the South African Medical Research Council at Wits University in South Africa published a novel and controversial paper in 1997 showing that other proteins within the bone matrix are also capable of initiating bone formation by induction.

In a series of incisive papers, the Bone Research Laboratory showed that the three mammalian transforming growth factor-β proteins (in short TGF-β), the TGF-β1, -β2, and –β3 that reside in the bone matrix together with the BMPs, can also initiate the induction of bone formation.

This remarkable property of the TGF-β proteins, however, only manifests in primate species, including the baboon Papio ursinus and the macaque Macaca mulatta.

The latest studies now indicate that the mammalian TGF-β proteins are determinant of the bone induction cascade, regulating and driving the expression of the homologous but molecularly different BMPs during the induction of bone formation in primate models. This may result in novel regenerative therapies by using either the TGF-β proteins singly or in combination with BMPs.

In another series of discoveries, the Bone Research Laboratory has also found that the implantation of macroporous devices made of calcium phosphate/hydroxyapatite in muscle tissue of non-human primates, surprisingly results in bone formation by induction.

In an important finding the South African-based team has also shown how macroporous calcium phosphate-based surfaces are modified or “primed” by osteoclasts (cells that resorb bone), in this way providing geometric cues that stimulate and regulate the differentiation of resident stem cells into bone forming cells, depositing new bone formation by induction.

No matter how counter-intuitive it may seem – to the scientist as well as the layman – the most effective route to induce bone using macroporous devices for bone replacement therapies is through the use of macroporous surfaces that set into motion a pronounced osteoclastic activity which will prime the biomaterial surfaces to stimulate osteoclastic activity leading to cell differentiation and the induction of bone formation. We have thus found that more osteoclastic activity, more surface modifications of the implanted devices with the net result of more bone formation.

The full paper detailing these findings is available here.