Abstract
Objective: Mice homozygous for targeted deletion of the gene encoding fibroblast growth factor receptor 3 (FGFR3−/−) develop kyphoscoliosis by 2 months of age. The first objective of this study was to use high resolution X-ray to characterize curve progression in vivo and micro CT to quantify spine architecture ex vivo in FGFR3−/− mice. The second objective was to determine if slow release of the bone anabolic peptide parathyroid hormone related protein (PTHrP-1-34) from a pellet placed adjacent to the thoracic spine could inhibit progressive kyphoscoliosis.Materials and methods: Pellets loaded with placebo or PTHrP-1-34 were implanted adjacent to the thoracic spine of 1-month-old FGFR3−/− mice obtained from in house breeding. X rays were captured at monthly intervals up to 4 months to quantify curve progression using the Cobb method. High resolution post-mortem scans of FGFR3−/− and FGFR3+/+ spines, from C5/6 to L4/5, were captured to evaluate the 3D structure, rotation, and micro-architecture of the affected vertebrae. Un-decalcified and decalcified histology were performed on the apical and adjacent vertebrae of FGFR3−/− spines, and the corresponding vertebrae from FGFR3+/+ spines.Results: The mean Cobb angle was significantly greater at all ages in FGFR3−/− mice compared with wild type mice and appeared to stabilize around skeletal maturity at 4 months. 3D reconstructions of the thoracic spine of 4-month-old FGFR3−/− mice treated with PTHrP-1-34 revealed correction of left/right asymmetry, vertebral rotation, and lateral displacement compared with mice treated with placebo. Histologic analysis of the apical vertebrae confirmed correction of the asymmetry in PTHrP-1-34 treated mice, in the absence of any change in bone volume, and a significant reduction in the wedging of intervertebral disks (IVD) seen in placebo treated mice.Conclusion: Local treatment of the thoracic spine of juvenile FGFR3−/− mice with a bone anabolic agent inhibited progression of scoliosis, but with little impact on kyphosis. The significant improvement in IVD integrity suggests PTHrP-1-34 might also be considered as a therapeutic agent for degenerative disk disorders.
Highlights
Scoliosis is a pathological condition characterized by lateral curvature of the spine in the coronal plane, whereas kyphosis is excessive angulation of the spine in the sagittal plane
The second objective was to determine if slow release of the bone anabolic peptide parathyroid hormone related protein (PTHrP-1-34) from a pellet placed adjacent to the thoracic spine could inhibit progressive kyphoscoliosis
Results:The mean Cobb angle was significantly greater at all ages in FGFR3−/− mice compared with wild type mice and appeared to stabilize around skeletal maturity at 4 months. 3D reconstructions of the thoracic spine of 4-month-old FGFR3−/− mice treated with PTHrP1-34 revealed correction of left/right asymmetry, vertebral rotation, and lateral displacement compared with mice treated with placebo
Summary
Scoliosis is a pathological condition characterized by lateral curvature of the spine in the coronal (front–back) plane, whereas kyphosis is excessive angulation of the spine in the sagittal (sideways) plane. The presence of scoliosis before the age of 5 years is defined as early onset scoliosis (EOS) and leads to severe, three dimensional deformation of the spine in ~1/2500 children. The deformity impedes normal lung development and contributes to the primary morbidity associated with the condition [3]. While the effects of EOS treatment on morbidity are not fully understood, it has been established that early fusion of the spine to prevent progression of the curve can be further detrimental to pulmonary health [4]. Alternative growth-sparing techniques that allow ongoing development of the spine and thoracic cage are encouraged. These techniques rely on bracing, serial casting, and in refractory cases the use of “growing rods” for www.frontiersin.org
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