Use and efficacy of bone morphogenetic proteins in fracture healing

Abstract

Purpose: This review evaluates the application of bone morphogenetic proteins (BMPs) in delayed bone repair, aiming at a broad audience from clinicians to scientists. Next to an overview of the role of the different BMPs, their antagonists and their current applications, special attention is focused on new scientific developments improving the effects of BMP-based therapy for bone repair.

Methods: Publication searches in PubMed and Embase revealed 850 relevant articles on the criteria 'BMP' AND 'bone repair' (as of May 2011). The abstracts were carefully reviewed and papers were selected according to the content.

Results: The resulting publications showed that BMP-2 and BMP-7 are clearly the most extensively evaluated BMPs, in general with positive results on bone healing, comparable to the use of unspecific preparations such as autologous bone grafts or platelet-rich plasma.

Conclusions: Although the efficacy of BMPs as stimulators of bone repair has been demonstrated in model systems and clinical studies, the use of BMPs to enhance fracture healing in the clinical setting is still controversial. Issues such as when, where and how much of which BMP is the most effective and profitable to use still have to be elucidated. But optimisation of the BMP products used in combination with cheaper production methods will inevitably stimulate the clinical use of BMPs for bone fracture healing in the near future.

Fig. 1

Schematic overview of BMP expression during different stages of fracture healing [74, 75]. The indicated days are dependent on the bone and fracture type

Fig. 2

Regulation of the BMP signalling pathway during bone formation. 1 BMP binds to BMP receptor type II (BMP-RII). 2 BMP/BMP-RII complexes with BMP receptor type I (BMP-RI), which is then phosphorylated. 3 BMP-RI phosphorylates the regulatory Smad1, Smad5 and Smad9, after which a complex is formed with Smad4. The complex is transported to the nucleus and the regulation of target genes occurs, leading to bone formation. Further regulation of the signalling pathway takes place at various levels. 4 Extracellular BMP inhibitors, e.g. chordin, noggin, Tsg, gremlin, follistatin and BMPER. 5 Receptor antagonists, e.g. BMP-3, BMP-13. 6 Membrane pseudo-receptors, e.g. BAMBI, CRIM1, and co-receptors, e.g. endoglin. 7 Intracellular inhibitors, e.g. Smad6, Smad7, Smad8b, Smurf1, Smurf2