Abnormal proliferation and differentiation of osteoblasts from girls with adolescent idiopathic scoliosis to melatonin

Abstract

Melatonin deficiency has been postulated as an etiologic factors in adolescent idiopathic scoliosis (AIS). In previous studies, melatonin was shown to regulate skeletal growth and bone formation in both humans and rats. Although it remains controversial whether there are differences in serum melatonin level between AIS and control subjects, melatonin signaling pathway dysfunction in osteoblasts has been reported in patients with AIS. Recently, our group found that melatonin receptor 1B (MT2) gene polymorphism was associated with the occurrence of AIS. Hence, the present study investigated the effect of melatonin on AIS osteoblasts. In vitro assays were performed with osteoblasts isolated from 17 severe AIS girls and nine control subjects. The osteoblasts were exposed to different concentrations of melatonin for 3 days. The effects of melatonin on cell proliferation (as evidenced by MTT assay) and differentiation (demonstrated by alkaline phosphatase activity) were determined. In the control group, melatonin significantly stimulated osteoblasts to proliferate and differentiate. However, in the AIS group, the stimulatory effects of melatonin were not discernible. Importantly, this finding demonstrated that there is a significant difference between AIS and control osteoblasts in functional response toward melatonin. Melatonin-stimulated proliferation of control osteoblasts was inhibited by the MT2 antagonist, 4-phenyl-2-propionamidotetraline, as well as by luzindole, a nonselective melatonin receptor antagonist, suggesting that MT2 is associated with the proliferative action of melatonin. The lack of response in AIS osteoblasts might be because of dysfunction of the melatonin signaling pathway, which may contribute to the low bone mineral density and abnormal skeletal growth observed in patients with AIS.

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

“…In some girls with AIS, a particular MLT-signaling defect is evident [17,256,258,337]. Correction of this defect in vitro by estradiol suggested that "the lack of estrogen that results in late menarche may be corrected by estrogen agonists having a positive effect on bone tissue remodeling" [256].…”

Adolescent idiopathic scoliosis: evidence for intrinsic factors driving aetiology and progression

“…However, in humans, studies have predominantly reported no difference in serum melatonin levels in patients with or without AIS [5,56], suggesting there would unlikely be any benefit to melatonin supplementation for patients with AIS. Critically, a more recent study has shown that melatonin can induce the proliferation of normal human osteoblasts but not osteoblasts from AIS female patients [37], suggesting an intrinsic dysfunction in melatonin signalling exists in human AIS spinal bone tissue. At present, the molecular basis for this intrinsic dysfunctional melatonin signalling is not fully understood.…”

Participation of sex hormones in multifactorial pathogenesis of adolescent idiopathic scoliosis

“…This spinal deformation occurs mostly among pubescent girls [4]. Many authors emphasize multifactorial pathomechanism of scoliosis [5][6][7][8], and the involvement of genetic and epigenetic predispositions, and the influence of hormonal factors are widely accepted [6,7,[9][10][11][12][13][14][15].…”