Étiopathogenèse de la scoliose idiopathique de l'adolescent : implication de la mélatonine et de l'ostéopontine

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis that affects a significant number of young teenagers, mainly females.  Historically, several hypotheses were postulated to explain the aetiology of AIS.  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 chickens, and more recently in rats maintained in a bipedal mode, produces 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.  We confirmed this defect by analysing more AIS patients and by using a new technology (cellular dielectric spectroscopy) which gives more precise results because it allows the measurement and analysis of receptor activation without the need to pretreat cells.  This technique showed the same functional classification into three functional groups as identified by cAMP technique.    Melatonin signalling dysfunction is caused by phosphorylation of serine residues affecting the activity of G inhibitory (Gi) proteins normally associated with melatonin receptors present at the cell surface.  This defect could be caused by an imbalance in the activity of kinases or phosphatases that can regulate Gi proteins phosphorylation.  Among these kinases PKCd was initially of interest because it has been shown that it can phosphorylate Gi proteins. We showed that this kinase interacts with melatonin receptor MT2 and that this interaction varies from one functional group to another. Thereafter, we moved one step further to characterise downstream effector regulated by melatonin.  This work has led to the identification of osteopontin (OPN) which is a relevant candidate because it can act as a mecanosensor and it is involved in proprioception, postural and vestibular control.  OPN was initially identified in pinealectomized chickens where it was shown to be upregulated at protein and mRNA levels only in scoliotic ones. We also used another animal model, C57Bl/6 mice which are naturally deficient in melatonin. We generated bipedal mice by amputating forelimbs of OPN knock-out mice, CD44 knock-out mice as well as C57Bl/6 wild type mice. Our results showed that all bipedal mice OPN Knock-out or CD44 Knock-out did not develop scoliosis contrasting with C57Bl/6 wt mice where 45% develop scoliosis.  These results prompted us to investigate the role of this protein in scoliosis etiopathogenesis in humans.  We showed an increase in the OPN circulating levels in AIS patients and this elevation correlates with disease severity.  Elevated plasma OPN levels were also found in the asymptomatic at-risk group (offspring of scoliotic patients), suggesting that these changes precede scoliosis onset.

Keyphrases: PKC delta, Scoliosis, Melatonin, Osteopontin, PKC delta, Diagnostic test