This was further corroborated by in situ analysis, showing an increased expression of Runx2 on the 7th day post injury in the mar row cavity. Day 14 post injury On day 14 post injury a marked increase of BV TV was detected Bortezomib order within the bone marrow cavity of lovastatin treated mice as compared with untreated mutants. Inhibitors,Modulators,Libraries A less pro nounced BV TV increase was also detectable in the cortical regions. Thus, lovastatin appears to accelerate cortical bone repair primarily by enhancing new bone formation within the bone marrow cavity and by replacing fibro cartilaginous tissue in the injury site with mineralised bone matrix. The associated trabecullar bone lining osteoblasts expressed Collagen type I and little Osteopon tin, which is characteristic of the mature osteoblast phe notype.

The osteoid thickening characteristic for Nf1Prx1 mice was no longer observed, indicating that osteoblast function was restored. Consist ent with the function of lovastatin as an indirect inhibitor of Ras prenylation, the Inhibitors,Modulators,Libraries bone pro anabolic effect of lovas tatin correlated with the normalisation of MAPK signal ling measured as a phospho Erk1 2 to Erk1 ratio Inhibitors,Modulators,Libraries in calvarial osteoblasts. Discussion Studies of Nf1 function in bone development and home ostasis have long been hampered by the lack of a suitable animal model. Recently, we have shown that bi allelic inactivation of the Nf1 gene in developing limbs leads to a phenotype which recapitulates features of NF1 associ ated bone dysplasia, including bowing of the tibia. Despite a striking decrease of the bone mineral content and increased bone porosity Nf1 inactivation does not result in spontaneous fractures.

We therefore decided to induce a bone injury in the Nf1 deficient limb in order to model aspects of NF1 associated tibial fractures and pseudarthrosis. The cortical bone injury model presented here uncovers an important role for Nf1 in the Inhibitors,Modulators,Libraries regulation of bone regeneration. The study by Yu and colleagues con ducted on Nf1 heterozygous mice revealed no dramatic changes in bone morphometric parameters and dynamics of bone formation. These results are in agreement with ours, as heterozygous Nf1flox Prx1Cre mice did not differ in the progression of injury repair from wild type mice. In contrast, Nf1 deficiency results in delayed osteoblast differentiation, leading to a retarda tion of the repair process.

This is paralleled by ectopic car tilage formation as well as an expansion of spindle shaped connective tissue fibroblasts, both also found in the NF1 pseudarthrosis tissue. In addition, our data show an increased number of osteoclasts at the injury site paralleled Inhibitors,Modulators,Libraries by an increased serum D PYD concentration in the mutant animals. Both effects are only marginally reduced by lovastatin enough treatment. The increase of osteoclast number in the injury site is similar to our previous finding of the increased osteoclast number in the chondro osseous junction.