Tibial dysplasia, which leads to fracture and pseudarthrosis, occurs in around 4% of children with NF1, and also in children with no underlying disorder. Pseudarthrosis of the fibular may or may not be present, or as an isolated entity, as can pseudarthrosis in the forearm (rare). Other bone problems faced by individuals with NF1 are scoliosis (20%), pectus excavatum/carinatum (12%), and sphenoid wing dysplasia (7%). Dural ectasia and plexiform neurofibromas can also affect the bone. The protein neurofibromin acts as a regulator of the Ras/MAPK pathway in all cells, and its loss leads to Ras overactivity.
An underlying bone phenotype has emerged: up to 30% of children with NF1 are osteopenic, with smaller bones and decreased stressstrain index. While bone homeostasis is often close to normal, bone healing at pseudarthrosis sites is grossly abnormal. Typically a low energy pathological fracture will occur in the anterolaterally bowed tibia, which will not heal despite immobilisation, with bone resorption and invasion of fibrous tissue dominating over bone formation.
Stevenson and others have shown that in at least some psuedarthroses, loss of heterozygosity has occurred rendering the tissue NF1−/−. We have created a model of local haploinsufficiency in a fracture by injecting NF1 floxed mice with a cre-bearing adenovirus. Much of the fibrous tissue that ensues is NF1−/−. Non-union occurs in most animals, along with typical findings of excessive bone resorption and multiple TRAP-positive cells in the fibrous tissue.
We have taken a pathway approach and a generic approach to rescuing the model. In the pathway approach we have blocked downstream kinases in the overactive pathway, including MEK and JNK. MEK inhibition has the unwanted effect of inhibiting endochondral ossification. JNK inhibition, especially when combined with BMP2, produces a high rate of union and a decrease in the amount of fibrous tissue. The generic approach of boosting bone formation with BMP2 and inhibiting resorption with zoledronic acid is also effective, with a high rate of union and reduced fibrous tissue invasion. Further translational work is required to conquer tibial pseudarthrosis and the accompanying disability it creates for children.
Disclosure: Receipt of grants/research support: Novartis, Amgen, Celgene, N8.
27 - 30 Jun 2015