Do estrogens impact adolescent idiopathic scoliosis?

Recent discoveries in the pathogenesis of adolescent idiopathic scoliosis (AIS) indicate that various hormones, especially estrogens, have a role in its onset and development. This role for estrogen seems possible because of its interaction with factors that influence the development and progression of this spinal deformity. Additionally, estrogens impact bone remodeling and growth, as well as bone acquisition, all of which are affected in AIS. Despite the fact that estrogens are not causative factors of AIS, they could impact the progression of spinal deformity by interacting with factors that modulate bone growth, biomechanics and structure. Thus, clarifying the role of estrogens is essential for understanding how AIS evolves during skeletal growth and for the development of new therapeutic interventions.

Estrogen cross-talk with the melatonin signaling pathway in human osteoblasts derived from adolescent idiopathic scoliosis patients.

Adolescent idiopathic scoliosis (AIS) represents the most frequently occurring form of scoliosis that occurs and progresses in puberty. This critical period coincides with many biological changes related to estrogens. The aim of this study was to determine the effect of 17-beta-estradiol on the responsiveness of AIS osteoblasts to melatonin and the cross-talk between estrogen and melatonin at the levels of the G(S)alpha and G(i)alpha proteins. Human osteoblasts derived from AIS (n = 40) and control patients (n = 10) were first screened for their functional response to the melatonin and 17-beta-estradiol. In response to the 17-beta-estradiol in a specific group of scoliotic patients, the level of 3',5'-cyclic adenosine monophosphate (cAMP) was significantly decreased when compared with the level observed in the presence of increasing concentrations of melatonin alone. Ours results provide strong evidence of the cross-talk between 17-beta-estradiol and melatonin signaling in human AIS osteoblasts. These results indicate a novel role for 17-beta-estradiol and melatonin in AIS, controlling the coupling of G(S)alpha protein and MT2 receptor on human osteoblasts. We found that the increased cAMP levels induced by melatonin can be corrected by the treatment of the cells with 17-beta-estradiol. Thus, estrogens or estrogen receptor agonists become important compounds to consider in AIS osteoblast cell functioning. Consequently, our results add a new facet to the understanding the role and function of melatonin in AIS.

[Etiopathogenesis of adolescent idiopathic scoliosis and new molecular concepts]. / Récents progrès dans l'étiopathogénie de la scoliose idiopathique de l'adolescent et nouveaux concepts moléculaires.

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis that affects a significant number of young teenagers, mainly females (0.2-6 % of the population). Historically, several hypothesis were postulated to explain the aetiology of AIS, including genetic factors, biochemical factors, mechanics, neurological, muscular factors and hormonal factors. The neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS has generated great interest. This hypothesis stems from the fact that experimental pinealectomy in chicken, and more recently in rats maintained in a bipedal mode, produces a scoliosis. The biological relevance of melatonin in idiopathic scoliosis is controversial since no significant decrease in circulating melatonin level has been observed in a majority of studies. Analysis of melatonin signal transduction in musculoskeletal tissues of AIS patients demonstrated for the first time a defect occurring in a cell autonomous manner in different cell types isolated from AIS patients suffering of the most severe form of that disease. These results have led to a classification of AIS patients in three different functional groups depending on their response to melatonin, suggesting that the cause of AIS involves several genes. Molecular analysis showed that melatonin signaling dysfunction is triggered by an increased phosphorylation of Gi proteins inactivating their function. This discovery has led to development of a first scoliosis screening assay. This test, using blood sample, is currently in clinical validation process in Canada and could be used for screening children at high risk of developing AIS.

Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis.

Presently, the genetic cause of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, remains unclear. Among many hypotheses, the neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS generated the greatest interest and controversy since no decrease in circulating melatonin level has been observed in a majority of studies. Previously, we have reconciled the role of melatonin in AIS by demonstrating a melatonin signaling dysfunction occurring in osteoblasts derived from AIS patients, which contrasted with similar cells isolated from healthy subjects. We found that this difference is caused in AIS cells by increased phosphorylation of serine residues affecting the activity of G inhibitory proteins normally associated with melatonin cell surface receptors. Here we propose a preliminary molecular classification of patients with AIS based on the cellular response to the melatonin (cAMP) and distinct protein-protein interactions. These interactions include those between protein kinase C delta (PKCdelta) and MT2 melatonin receptors or PKCdelta and the receptor for activated protein C kinase 1. This finding could help in future molecular classification of patients with AIS.