Background: Recombinant bone morphogenic proteins (BMPs) are potent bone anabolic agents suggested for the treatment of orthopaedic complications associated with neurofibromatosis type 1 (NF1), in particular, congenital pseudarthrosis of the tibia. We have explored the effect of Nf1 haploinsufficiency on ex vivo and in vivo models of BMP-induced bone formation in Nf1+/− mice.

Methods: Using an Nf1+/− knockout mouse model, we expanded primary cell cultures from calvarial and long bone osteoblasts and measured osteogenic markers, such as alkaline phosphatase and mineralization using Alizarin Red staining, and the responses of these markers to BMP-2 treatment. We also developed an in vivo muscle pouch heterotopic ossification model to assess the ability of BMP-2 to form bone.

Results: Primary osteoblast cultures from Nf1+/− mice showed reduced ALP staining, ALP activity and mineralization, denoting an anabolic deficiency. Nf1+/− osteoblasts responded to BMP-2 treatment, although osteogenic markers were reduced compared to BMP-2 treated Nf1+/+osteoblasts. Heterotopic bone was induced in both genotypes by surgically implanting BMP-2, however less bone was formed in Nf1+/− mice than Nf1+/+ controls.

Conclusion: These data indicate that BMP therapies have potential utility in treating orthopaedic defects in children with NF1, but that dosing may need to be optimized for this patient subgroup or that catabolism may need to be also controlled.