Study of Pathomechanisms Initiating Scoliotic Deformities: Identification of a Novel Factor Essential for the Initiation and Progressive of Scoliosis
Introduction: Melatonin signaling dysfunction in AIS patients (Spine, 29:1772-1781, 2004)and melatonin deficiency could both induce a scoliosis suggesting that the asymmetrical growth of the spine involves a common downstream effector regulated by melatonin. This study was then designed to identify this triggering factor.
Methods: 100 newly hatched chickens underwent a complete removal of the pineal gland. Sham (n=20)and intact chicken (n=25)were used as controls. All chicken underwent radiographic examination and were sacrificed at day 28 to collect tissues for RNA expression analysis by RT-PCR and proteins were examined by Western blot analysis. Bipedal C57Bl/6 mice (n=50) were generated by surgery and examined by the same methods. Sera of mice, AIS patients and matched healthy controls were also analyzed to determine the levels of circulating P factor using an ELISA assay.
Results: A strong expression of a gene encoding a protein, termed P factor, was detected only in paraspinal muscles of pinealectomized chicken developing a scoliosis. Accumulation of P factor was also confirmed at the protein level by Western blot analysis. Bipedal C57Bl/6 mice, which are melatonin deficient, developed also scoliotic deformities in a proportion of 45% over a 2-months period. Interestingly, genetically modified C57Bl/6 mice devoid of P factor (n=60) or its receptor (n=40)did not develop a scoliosis. Moreover, P factor circulating levels in scoliotic patients showed a 2-4 fold increase when compared to healthy matched individuals.
Conclusions: The study of molecular changes in animal models led us to identify a novel factor, which is essential to initiate scoliosis through a specific signalling action. The clinical relevance of the P factor in AIS is further strengthened by the detection of higher levels of P factor only in scoliotic patients and could lead to the development of the first pharmacological therapies to prevent scoliosis formation or stop its progression.
Hibbs Award Nominee for Best Basic Science Paper