The aetiology of the condition has never been well established, and its exact cause is unknown. Thera peutic programs have been largely based on conceptual considerations for the treatment of post traumatic non unions. These forms of treatment, however, more are often futile when applied to pseudarthrosis of the tibia indicat ing that systemic problems interfere with normal healing. In some cases amputation is the only option. In order to better understand neurofibromin func tion in bone we recently generated mice bearing a homozygous Nf1 inactivation in the embryonic limb and in the cranial mesenchyme. The affected Inhibitors,Modulators,Libraries cell types include endothelial cells, chondrocytes and osteoblasts but not osteoclasts, which are of haematopoietic origin.

Interest ingly, early limb bud specific Nf1 inactivation results in tibia bowing similar to that observed in NF1 patients. However, since in the mouse model the affected extremi ties are not subjected to excessive mechanical force, bone fracture and the expected pseudarthrosis never occur spontaneously. In order to study Inhibitors,Modulators,Libraries the role of Nf1 in the reg ulation of bone repair we applied a previously described bone injury model, which has been designed for the com parative analysis of the bone healing in wild type versus knock out mice. The model involves drilling 0. 5 mm holes through the entire diameter of the tibial diaphysis, which does not lead to bone shaft breakage, as the remaining cortical structure stabilises the bone collar. Despite the small size of the injury, the experimental model enables both qualitative and quantitative analysis of the complex process Inhibitors,Modulators,Libraries of bone repair.

At the same time it causes the least possible distress to the tested animals. The normal repair process involves stages of haematoma Inhibitors,Modulators,Libraries for mation, connective tissue fibroblast and mesenchymal stem cell recruitment followed by osteoblast differentia tion. Consequently, bone formation in the course of the injury repair relies on the timely recruitment and differen tiation of mesenchymal progenitor cells within the injury site. These processes appear disturbed in Nf1Prx mice leading to a delay of cortical bone regeneration accompa nied by the accumulation of the fibro Inhibitors,Modulators,Libraries cartilaginous tissue in the site of injury. The findings match patho histological descriptions of the NF1 pseudarthrosis in the literature, where pseudarthrotic tissue is characterised as osteoid rich, fibro cartilaginous and highly vascularised tissue.

In the search for a possible therapeutic intervention as customer review well as for the molecular mechanism of the disease, we tested the influence of statins on the process of bone repair in the Nf1Prx1 mouse model. Statins are inhibitors of 3 hydroxy 3 methylglutaryl coen zyme A reductase, broadly used for the reduction of serum cholesterol.