Bone Morphogenetic Protein 7 (BMP7) is a powerful osteoinductive substance that could stimulate bone formation in difficult conditions including distraction osteogenesis. However, to be effective, large unphysiological doses are required. Blocking the expression of BMP antagonists could amplify the effects of BMP7, allowing smaller doses of BMP7 to be used without altering its osteogenic potential. In this study, BMP7 antagonist Noggin was shown to be upregulated following BMP7 injection in a rabbit distraction osteogenesis model suggesting a role for Noggin in controlling BMP7 activity. Blocking Noggin expression may thus permit smaller doses of BMP7 to be used effectively.

Distraction osteogenesis (DO) is an excellent method to form new bone. However, the long duration the external fixator has to be kept on until the new bone consolidates, could lead to numerous problems. BMP7 may accelerate bone formation in DO. However, large doses of BMP7 may be necessary. In this study, we investigated the expression of BMP7 antagonist Noggin in DO.

Noggin may control BMP7 activity through a negative feedback mechanism. Blocking Noggin may amplify the effects of BMP7, thus permitting the use of smaller doses of BMP7 effectively in DO.

Using smaller doses of BMP7 – while maintaining its powerful effects – may decrease side effects and render this drug more affordable economically.

Noggin is normally expressed in DO. Its expression is upregulated by local application of BMP7. Its expression is co-localized to the same cells that express BMP7 and its receptors.

The right tibia of sixteen rabbits was lengthened using a uniplanar fixator. The rabbits were divided into two groups: one received seventy-five micrograms recombinant BMP7 and the other placebo. All injections were performed one week after start of distraction. Rabbits were sacrificed ten minutes, one day, two days and two weeks following the injections. The expression of Noggin was studied in the distracted tissue by immunohistochemistry.

Noggin may play a role in DO. Blocking its action may have huge clinical implications, by permitting the use of smaller – but equally effective – amounts of BMP7.

Funding: CIHR, FRSQ and Shriners of North America

The different pathways by which bone morphogenetic protein 7 (BMP-7) could exert its osteogenic function in distraction osteogenesis (DO) were investigated. Using immunohistochemistry, the temporal and spatial expression of markers for angiogenesis, cell proliferation, Indian hedgehog pathway, osteogenic growth factors and their receptors were investigated in a rabbit model of DO. Our results showed that local injection of BMP-7 at the lengthened site caused up-regulation of expression of growth factors and their receptors, cell proliferation and vascular markers and Indian hedgehog gene in a temporal fashion. By knowing these pathways, manipulation of DO by pharmaceutical agents may be possible.

Based on preliminary data, BMP-7 can accelerate the consolidation of newly formed bone if locally injected early in the distraction phase; however, the exact mechanism remains unknown.

The purpose of this study was to investigate the different pathways through which BMP-7 exerts its effects in DO.

The right tibia of twenty-four rabbits was lengthened 2.0 cms. The rabbits were divided into three groups : control, placebo and treated groups. The rabbits received no injection (control), buffer (placebo) and 75 micro grams BMP7 (treated) in the distracted zone one week after the start of distraction. The rabbits were sacrificed ten minutes, one day, two days and two weeks following the injections. Using immunohistochemistry, the different pathways of bone formation were assessed by analysing the expression of markers for angiogenesis (VGEF, Vascular Endothelial Growth Factor and PECAM , platelet endothelial cell adhesion molecule) , cell proliferation markers (PCNA, proliferation cell nuclear antigen), osteogenic growth factors (TGFβ, IGF, FGF and their receptors) and Indian hedgehog gene as part of the parathyroid hormone related peptide pathway.

BMP-7 may stimulate bone formation through several pathways in a temporal fashion early after local injection, by up-regulating the expression of numerous osteogenic growth factors and their receptors and Indian hedgehog, and late two weeks after the injection, by up-regulating cell proliferation and vascular markers.

Our results showed the possible mechanisms of action of BMP-7 in DO and more importantly the various pathways through which pharmacological agents could be used in the manipulation of DO.