Toward a Molecular Understanding of the Role of Melatonin in Adolescent Idiopathic Scoliosis Etiopathogenesis

• a - The Yves Cotrel Foundation (Paris, France)

Purpose: We have recently reported a dysfunction of melatonin signaling in bone and muscle-forming cells of patients with adolescent idiopathic scoliosis (AIS) suggesting that pathology is rather caused by an aberrant transmission of melatonin signal than by its deficiency. The aim of this study was to further characterize the molecular mechanisms causing such dysfunction in AIS.

Methods: Primary cell cultures were prepared from musculoskeletal tissues of AIS patients (n=45) and ageand gender-matched controls (n=17) obtained intraoperatively. Different functional and complementary assays were performed to determine the mechanisms whereby melatonin signal transduction is impaired in severely affected AIS patients.

Results: Functional assays with a non-hydrolysable GTP analogue indicated a hypofunctionality of Gi proteins in AIS osteoblasts. Indeed, co-IP assays revealed that such inactivation of Gi proteins was caused by an aberrant phosphorylation of serine residues caused by a loss-of function of a specific phosphatase. Moreover, the role of that specific phosphatase is further strengthened by the detection of mutations, which may interfere with its functions.

Conclusion: This demonstrates that a melatonin signaling dysfunction occurs in AIS due to an increased phosphorylation of Gi proteins. We have found a phosphatase involved in that process although it cannot be ruled-out that mutations in other proteins known to modulate Gi protein activity could cause a similar signaling defect in other AIS patients. This should lead to the development of the first functional assay to identify children at risk to develop AIS. The relevance of the proposed mechanism causing this melatonin signaling dysfunction is further supported by the fact that our candidate gene is already localized in a locus of susceptibility for AIS.

• If noted the author indicates something of value received. The codes are identified as: a-research or institutional support; b-miscellaneous funding; c-stock or stock options; d-royalties; e-other financial or material support including consulting.