Bone Abstracts

Neurofibromatosis type 1 (NF1) is a genetic disorder with an incidence of 1/3000. Inactivating mutations in the NF1 gene cause Ras-MEK overstimulation, and predisposes NF1 patients to cancer. A new generation of MEK inhibitors (PD0325901 and AZD6244) are under clinical trials in cancer patients, including NF1 patients. Congenital pseudarthrosis of the tibia is a major complication for NF1 patients, and associates with loss-of-heterozygosity of the NF1 gene. The primary aim of this study is to assess the impact of clinically available MEK inhibitors on bone homeostasis and fracture healing. The secondary aim of this study is to assess whether the MEK inhibitor PD0325901 is able to inhibit Ras-MEK over-activity and thus promote fracture healing in a mouse model of NF1 pseudarthrosis.

C57/Bl6 mice underwent a tibial midshaft fracture, and were treated with PD0325901 or AZD6244 at 10 mg/kg once a day. PD0325901 increased cartilage deposition by 60% at day 10 after fracture, compared with a 20% increase with AZD6244. Treatment with PD0325901 significantly expanded the hypertrophic zone in the growth plate of the mice, while AZD6244 showed a trend. Treatment with MEK inhibitors also lead to a significant decrease in osteoclast surface at the growth plate and the fracture callus.

To determine whether MEK inhibition could help treat NF1 pseudarthrosis, we adapted a published NF1 pseudarthrosis model, and co-delivered rhBMP2 with PD0325901. Mice were treated with vehicle, PD0325901, rhBMP2, or PD0325901+rhBMP2, resulting in union rates of 0, 8, 69 and 80%, respectively. Co-delivery also resulted in a two-fold increase in bone formation and significantly larger calluses compared to rhBMP2 treatment alone.

These studies show that MEK inhibitors have powerful effects on the skeletal system, leading to changes in cartilage homeostasis, and systemic osteoclast reduction. These compounds may be therapeutically beneficial in NF1 pseudarthrosis, where they act synergistically with rhBMP2 to promote bone formation and fracture healing.