Molecular Classification of AIS Patients: Toward New Emerging Concepts in Molecular Medicine to Treat Adolescent Idiopathic Scoliosis

Summary: Identification of a melatonin signaling dysfunction in cells of AIS patients allowed the establishment of a molecular classification of AIS patients and the identification of therapeutic compounds able to rescue such defect.

Introduction: At present, there is no proven method or test available to identify children at risk of developing AIS or to identify which of the affected individuals are at risk of progression. We have recently demonstrated a melatonin signaling dysfunction in cells derived from AIS patients. The goals of that study were to assess the possibility to establish a molecular classification of AIS patients and to demonstrate the feasibility to correct this melatonin signaling defect using therapeutic compounds.

Methods: The melatonin signal transduction pathway functionality was investigated in osteoblasts derived from biopsies taken intraoperatively from a series of patients clinically well-defined with AIS (n=36) and compared with a series of age- and gender-matched subjects presenting another type of scoliosis or none (n=14). Osteoblast cultures were treated in presence of varying concentration of melatonin alone or in presence of 2.5 _M of different therapeutic compounds (the nature of both compounds tested cannot be disclosed at this stage). The cAMP content was determined in duplicate using an enzyme immunoassay kit (Amersham-Pharmacia Biosciences).

Results: Osteoblasts from patients with AIS showed a lack or a markedly reduced inhibition of forskolin-stimulated adenylyl cyclase activity by melatonin when compared with normal cells. Interestingly, treatment with compound A rescued melatonin signal defect in cells derived from 36% of AIS patients while the second compound tested (B) rescued melatonin signaling in 47% of AIS patients. Overall, melatonin signal transduction was restored in cells of 64% of AIS patients (23/36) when treated by one of these therapeutic compounds.

Conclusions: These results showed the feasibility of correcting the melatonin signaling dysfunction observed in cells derived from AIS patients. This study opens new clinical research avenues to assess the efficacy of therapeutic compounds to prevent or reduce scoliotic deformities.