2. Fracture healing in osteoporotic bone

(II) Fracture healing in osteoporotic bone

The healing of skeletal defects, be it fractures, be it defects from trauma or surgical interventions, follows a well defined process passing a few distinct steps. The first phase of the healing process is an inflammation with blood clotting and subsequent removal of the clot and eventual debris and bacteria. During this phase, the repair site is invaded by lymphoid and monocyte/ macrophage cells. The tissue becomes hypoxic and is characterized by an acidic pH. After induction of vascularization (no repair without vessels), mesenchymal progenitor cells are attracted to the repair site, where they differentiate into chondrocyte-or osteoblast lineage cells, depending on the rigidity of the fixation of the defect. This primary bone formation (woven bone) is followed by a remodeling phase, consisting in the removal of the woven bone and replacement by mechanically more stable lamellar bone.
In clinical situation where bone formation needs to be accelerated but without the intention to use bone substitute materials, growth factors like Bone Morphogenetic Protein-2 (BMP2) are applied, even though unphysiologically high amounts are required. We studied gene expression during the healing of a well defined, limited bone defect and found concomittant expression of BMPs and their antagonists in non-rigidly fixed fractures, while expression of BMP-antagonists remained low at rigidly fixed defect sites (Montjovent MO et al.). This data led to the hypothesis that endogenously released BMP antagonists might impair the biological efficacy of endoor exogenous growth factor. Indeed, we could demonstrate that an engineered BMP2 variant which binds and inactivates BMP antagonists, but which does not elicit a BMP signaling cascade, was able to increase the biological efficacy of exogenously added BMP2 (Sebald HJ et al.; Albers CE et al.). Extending these studies, we investigate the kinetics of bone repair by assessing the
transcriptome in dependence of time. To assess, whether osteoporosis and treatment of the disease with the anti-resorptive drug Alendronate (a bisphosphonate) would affect bone healing, we ovariectomized (OVX) young adult mice, treated them after 8 weeks with Alendronate for 5 weeks and then introduced a controlled osteotomy on the left femur which was either rigidly or non-rigidly fixed. After predefined time periods, the repair tissue was excised and total RNA was prepared for transcritpomics.

Analysis of the data is presently under way.

References:

- Montjovent MO et al. (2013) Expression of antagonists of WNT and BMP signaling after non-rigid fixation of osteotomies. Bone 53:79-86. (download pdf)
- Sebald HJ et al. (2012) Inhibition of endogenous antagonists with an engineered BMP-2 variant increases BMP-2 efficacy in rat femoral defect healing. Acta Biomater 8:3826-20. (download pdf)
- Albers CE et al. (2012) L51P – a BMP2 variant with osteoinductive activity via inhibition of Noggin. Bone 51:401-6. (download pdf)