Melatonin signaling dysfunction in adolescent idiopathic scoliosis.
METHODS
In vitro assays were performed with bone-forming cells isolated from 41 patients with adolescent idiopathic scoliosis and 17 control patients exhibiting another type of scoliosis or none.


OBJECTIVE
To determine whether a dysfunction of the melatonin-signaling pathway in tissues targeted by this hormone is involved in adolescent idiopathic scoliosis.


BACKGROUND
Pinealectomy in chicken has led to the formation of a scoliotic deformity, thereby suggesting that a melatonin deficiency may be at the source of adolescent idiopathic scoliosis. However, the relevance of melatonin in the etiopathogenesis of that condition is controversial because most studies have reported no significant change in circulating levels of melatonin in patients with adolescent idiopathic scoliosis.


METHODS
Primary osteoblast cultures prepared from bone specimens obtained intraoperatively during spine surgeries were used to test the ability of melatonin and Gpp(NH)p, a GTP analogue, to block cAMP accumulation induced by forskolin. In parallel, melatonin receptor and Gi protein functions were evaluated by immunohistochemistry and by coimmunoprecipitation experiments.


RESULTS
The cAMP assays demonstrated that melatonin signaling was impaired in osteoblasts isolated from adolescent idiopathic scoliosis patients to different degrees allowing their classification in 3 distinct groups based on their responsiveness to melatonin or Gpp(NH)p.


CONCLUSIONS
Melatonin signaling is clearly impaired in osteoblasts of all patients with adolescent idiopathic scoliosis tested. Classification of patients with adolescent idiopathic scoliosis in 3 groups based on functional in vitro assays suggests the presence of distinct mutations interfering with the melatonin signal transduction. Posttranslational modifications affecting Gi protein function, such as serine residues phosphorylation, should be considered as one possible mechanism in the etiopathogenesis of AIS.
Research Center, Sainte-Justine Hospital, Bone Molecular Genetics and Musculoskeletal Malformations Laboratory, Montreal, Quebec, Canada. amoreau@justine.umontreal.ca
Alain
A
Moreau
Da Shen
DS
Wang
Steve
S
Forget
Bouziane
B
Azeddine
Debora
D
Angeloni
Franco
F
Fraschini
Hubert
H
Labelle
Benoît
B
Poitras
Charles-Hilaire
CH
Rivard
Guy
G
Grimard
D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D002478:Cells, Cultured; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006165:Guanylyl Imidodiphosphate; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008550:Melatonin / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism*; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D012600:Scoliosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008550:Melatonin