It has been well documented that statins induce a direct bone anabolic effect, which trans lates into accelerated bone healing in rats and mice. In particular, simvastatin, mavastatin, fluvastatin and lovastatin have all been shown to stimulate bone forma tion. Statin induced find FAQ bone formation is associated with increased osteoblast differentiation as measured by alkaline phosphatase, bone morphogenic protein 2 and osteocalcin expression. In addition, results of in vitro experiments indicate that statins might inhibit bone resorption by interfering with osteoclast function in a similar way as bisphosphonates. Both drug groups inhibit the mevalonate pathway albeit at dif ferent synthesis pathway levels, thus their mechanisms of action overlap.

The clinical relevance of this remains unclear as several independent studies were published presenting contradictory results on the fracture risk reduc tion assessment in lovastatin treated patients. Inde Inhibitors,Modulators,Libraries pendently of the bone anabolic and putative anti catabolic properties, a potential usefulness of statins in Inhibitors,Modulators,Libraries the treatment of NF1 was suggested by the Inhibitors,Modulators,Libraries improvement of learning dysfunction in Nf1 mice. Conse quently, statins became our first choice for the treatment of the delayed bone injury repair in Nf1Prx1 mice. Here we present data showing that a high dose of systemically applied lovastatin improves bone repair in Nf1Prx1 mice. This is probably a result of normalisation of mitogen acti vated protein kinase signalling and enhanced Runx2 expression. Methods Animal procedures The Nf1flox and Prx1Cre lines Inhibitors,Modulators,Libraries were maintained by contin uous backcrossing to wild type C57BL 6J mice to mini mise genetic drift.

The female Nf1flox mice were crossed to male Nf1flox heterozygous Prx1 Cre positive males. Mice were genotyped as described previously. We used Inhibitors,Modulators,Libraries 12 14 week old mice for cortical bone injury exper iments, essentially as described in with minor modifi cations. In brief, mice were anaesthetised by intraperitoneal injection of ketanest rompun. The skin was shaved and skin incision made over the medial aspect of the proximal end of the tibia. Soft tissue was cleared away and a hole through the tibia was made with a 0. 5 mm stainless steel drill. The drill site was placed at the level of the distal end of the tibial crest through the entire diameter of the tibia, that is, through medial and lateral cortices and the intervening medulla.

The skin was closed using acrylic histo glue. Lovastatin was converted into its active sodium salt form as described previously. In brief, selleck chem Cisplatin 50 mg mevinolin in the lactone form was dissolved in 1 ml prewarmed ethanol and 500 l of 0. 6 M NaOH was added. The solu tion was briefly vortexed and 10 ml of water was added. The solution was incubated for 30 minutes at room tem perature. The final mevinolin solution was adjusted to pH 8 with HCl and stored in multiple aliquots at 20 C. The treated group received daily oral gavage of 0.