Primary osteopathy of vertebrae in a neurofibromatosis type 1 murine model

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutation of the NF1 tumor suppressor gene. Spinal deformities are common skeletal manifestations in patients with NF1. To date, the mechanism of vertebral abnormalities remains unclear because of the lack of appropriate animal models for the skeletal manifestations of NF1. In the present study, we report a novel murine NF1 model, Nf1flox/−;Col2.3Cre+ mice. These mice display short vertebral segments. In addition, a significant reduction in cortical and trabecular bone mass of the vertebrae was observed in Nf1flox/−;Col2.3Cre+ mice as measured by dual-energy X-ray absorptiometry (DEXA) and peripheral quantitative computed tomography (pQCT). Peak stress and peak load were also significantly reduced in Nf1flox/−;Col2.3Cre+ mice as compared to controls. Furthermore, the lumbar vertebrae showed enlargement of the inter-vertebral canal, a characteristic feature of lumbar vertebrae in NF1 patients. Finally, histologic analysis demonstrated increased numbers of osteoclasts and decreased numbers of osteoblasts in the vertebrae of Nf1flox/−;Col2.3Cre+ mice in comparison to controls. In summary, Nf1flox/−;Col2.3Cre+ mice demonstrate multiple structural and functional abnormalities in the lumbar vertebrae which recapitulate the dystrophic vertebral changes in NF1 patients. This novel murine model provides a platform to understand the cellular and molecular mechanisms underlying the pathogenesis of spinal deficits in NF1 patients.

Research highlights► A novel murine model exhibiting dystrophic/non-dystrophic vertebral defects of NF1. ► Nf1flox/−;Col2.3Cre+ mice display short vertebral segments and less bone mass Nf1flox/−;Col2.3Cre+ mice show reduced peak stress and load. ► Enlargement of the lumbar spinal canal in Nf1flox/−;Col2.3Cre+ mice. ► Altered osteoclast and osteoblast numbers in the Nf1flox/−;Col2.3Cre+ vertebrae.