Analysis of Melatonin Transduction Pathway in Adolescent Idiopathic Scoliosis

(a – Fondation Yves Cotrol Di L’Institut Di France)

Purpose: The aim of this study is to determine whether adolescent idiopathic scoliosis (AIS) could be caused by a dysfunction of the melatonin-signaling pathway in tissues targeted by this hormone. Several works have been oriented toward a neuroendocrine hypothesis suggesting a melatonin deficiency as the source of AIS. However, the relevance of melatonin in AIS etiopathogenesis is controversial since no significant change in circulating level of melatonin has been observed in most of AIS patients.

Methods: Primary cell cultures were prepared from musculoskeletal tissues of AIS patients (n=15) and age- and gendermatched controls (n=8) obtained intraoperatively during spine surgeries. The cultures were used to test the ability of melatonin to block cAMP accumulations induced by forskolin. This inhibitory effect is mediated by melatonin signaling through membranous receptor coupled to G inhibitory proteins.

Results: Initial efforts have been focused on the osteoblasts since these bone-forming cells are known to respond to melatonin. Experimental data showed that the osteoblasts isolated from AIS patients are not responding to melatonin even at pharmacological doses, which contrasted with the normal cells. Indeed, the cAMP assay demonstrated that melatonin signaling were severely impaired in cells isolated from AIS patients (15/15) and in 2 cases (2/15) addition of melatonin resulted in the opposite effect by increasing the formation of cAMP by 125% and 200% respectively.

Conclusion: Taken together these results demonstrate for the first time that melatonin signaling is impaired in osteoblastic cells isolated from 100% of AIS patients tested. In 2 cases, the results strongly suggest the presence of activating mutations causing a more dominant form of AIS. This is further supported by the fact that these 2 patients are the only ones among those tested presenting an AIS family history. These results are clinically relevant and should lead to the development of innovative diagnostic tools and pharmacological approaches to prevent and cure AIS.

· If noted, the author indicates something of value received. The codes are identified as: a-research or institutional support; b-miscellaneous funding; c-royalties; d-stock options.