Fig 2 - available from: BMC Musculoskeletal Disorders
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X-ray films of bipedal rats in Group A and Group B 6 months after surgery. The scoliosis was more severe in the Luzindole-injected bipedal rats
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Abstract Background An ideal animal model has always been the key to research the pathogenesis and treatment of adolescent idiopathic scoliosis (AIS), while available methods have obvious disadvantages. The deficiency of melatonin has been proved relating to AIS. In this research, we intended to apply Luzindole, the melatonin antagonist, in bipedal...
Context in source publication
Context 1
... A was signifi- cantly higher than that in Group B (P < 0.05), but the difference in the severity of scoliosis was non-significant ( Fig. 1). At 6 months after surgery, the scoliosis rate in Group A was significantly higher than that in Group B (P < 0.05), and the Cobb's angle of Group A was significantly greater than that of Group B (P < 0.05) ( Fig. 1; Fig. 2). During the whole experiment, rats in Group C did not show any scoliosis, and the Cobb's angle of Group C was significantly smaller than those of Group A and Group B at any time point (P < 0.05) ( Table ...
Citations
... Studies however have continued to be published using bipedal rodent models particularly in scoliosis studies (Table 1), [2][3][4][5][6][7][8][9][10][11] with limited new information generated applicable to human IVDD. ...
Animal models have been invaluable in the identification of molecular events occurring in and contributing to intervertebral disc (IVD) degeneration and important therapeutic targets have been identified. Some outstanding animal models (murine, ovine, chondrodystrophoid canine) have been identified with their own strengths and weaknesses. The llama/alpaca, horse and kangaroo have emerged as new large species for IVD studies, and only time will tell if they will surpass the utility of existing models. The complexity of IVD degeneration poses difficulties in the selection of the most appropriate molecular target of many potential candidates, to focus on in the formulation of strategies to effect disc repair and regeneration. It may well be that many therapeutic objectives should be targeted simultaneously to effect a favorable outcome in human IVD degeneration. Use of animal models in isolation will not allow resolution of this complex issue and a paradigm shift and adoption of new methodologies is required to provide the next step forward in the determination of an effective repairative strategy for the IVD. AI has improved the accuracy and assessment of spinal imaging supporting clinical diagnostics and research efforts to better understand IVD degeneration and its treatment. Implementation of AI in the evaluation of histology data has improved the usefulness of a popular murine IVD model and could also be used in an ovine histopathological grading scheme that has been used to quantify degenerative IVD changes and stem cell mediated regeneration. These models are also attractive candidates for the evaluation of novel anti‐oxidant compounds that counter inflammatory conditions in degenerate IVDs and promote IVD regeneration. Some of these compounds also have pain‐relieving properties. AI has facilitated development of facial recognition pain assessment in animal IVD models offering the possibility of correlating the potential pain alleviating properties of some of these compounds with IVD regeneration. Animal models of IVD deneration have yielded invaluable information on the pathobiology of this degenerative condition and identified prospective therapeutic targets.The complexity of the degenerative changes and multiple therapeutic targets identified by these models suggests artificial intelligence methodology may be required to unravel these complexities and provide a rationale way forward in the development of effective repair strategies.
... Pathogenesis of AIS was studied in the bipedal/melatonin-reduced mouse [79] and rat [80] models. These experiments addressed whether melatonin is crucial for AIS development in mammals and whether the vertical load affects spine formation after pineal gland ectomy. ...
... To answer these questions, the authors created bipedal rats by resection the forelimbs and tail, and treated one group with a melatonin antagonist (Luzindole). The study concluded that a decreased melatonin level is not the primary cause of scoliosis, but that it may increase the likelihood and severity of scoliosis [80]. However, the value of the above models is questionable cosidering that "idiopathic-type scoliosis is not exclusive to bipedalism" [81,82]. ...
Adolescent idiopathic scoliosis (AIS) affects 2–3% of children. Numerous hypotheses on etiologic/causal factors of AIS were investigated, but all failed to identify therapeutic targets and hence failed to offer a cure. Therefore, currently there are only two options to minimize morbidity the patients suffering AIS: bracing and spinal surgery. From the beginning of 1960th, spinal surgery, both fusion and rod placement, became the standard of management for progressive adolescent idiopathic spine deformity. However, spinal surgery is often associated with complications. These circumstances motivate AIS scientific community to continue the search for new etiologic and causal factors of AIS. While the role of the genetic factors in AIS pathogenesis was investigated intensively and universally recognized, these studies failed to nominate mutation of a particular gene or genes combination responsible for AIS development. More recently epigenetic factors were suggested to play causal role in AIS pathogenesis. Sharing this new approach, we investigated scoliotic vertebral growth plates removed during vertebral fusion (anterior surgery) for AIS correction. In recent publications we showed that cells from the convex side of human scoliotic deformities undergo normal chondrogenic/osteogenic differentiation, while cells from the concave side acquire a neuronal phenotype. Based on these facts we hypothesized that altered neural crest cell migration in early embryogenesis can be the etiological factor of AIS. In particular, we suggested that neural crest cells failed to migrate through the anterior half of somites and became deposited in sclerotome, which in turn produced chondrogenic/osteogenic-insufficient vertebral growth plates. To test this hypothesis we conducted experiments on chicken embryos with arrest neural crest cell migration by inhibiting expression of Paired-box 3 (Pax3) gene, a known enhancer and promoter of neural crest cells migration and differentiation. The results showed that chicken embryos treated with Pax3 siRNA (microinjection into the neural tube, 44 hours post-fertilization) progressively developed scoliotic deformity during maturation. Therefore, this analysis suggests that although adolescent idiopathic scoliosis manifests in children around puberty, the real onset of the disease is of epigenetic nature and takes place in early embryogenesis and involves altered neural crest cells migration. If these results confirmed and further elaborated, the hypothesis may shed new light on the etiology and pathogenesis of AIS.
... The development of idiopathic scoliosis is associated with melatonin deficiency. The application of a melatonin antagonist was shown to improve the success rate of treating a bipedal rat scoliosis model, indicating that melatonin deficiency may increase the likelihood and severity of scoliosis [3]. A prospective study on adolescent idiopathic scoliosis found that melatonin supplements may prevent the progression of scoliosis, especially in mild cases with a curve of < 35 degrees [4]. ...
Aims:
Idiopathic scoliosis is a common deformity of the spine that has an especially high incidence rate in adolescents. Some studies have demonstrated a close relationship between idiopathic scoliosis and melatonin deficiency. Our team's previous research showed that melatonin can inhibit the proliferation of osteoblasts, but the mechanism remains unclear. This study aimed to determine the mechanism by which melatonin inhibits the proliferation of osteoblasts.
Main methods:
Cell viability experiment, DNA fragment detection and alkaline phosphatase (ALP) activity assays were performed to determine the effects of melatonin on the proliferation, apoptosis and differentiation of osteoblasts. We used immunofluorescence to detect the expression of STIM1 in melatonin-treated osteoblasts. STIM1 interference was achieved using a specific siRNA, and a TRPC inhibitor was used to block the influx of Ca2+. The mRNA expression was determined by RT-qPCR, and protein levels were measured by Western blot.
Key findings:
In this study, we found that melatonin inhibited the proliferation, differentiation and apoptosis of osteoblasts in a concentration-dependent manner. Additional studies showed that melatonin elevated cytosolic calcium levels by upregulation of STIM1, leading to osteoblast apoptosis via the mitochondrial pathway. Finally, we demonstrated that the STIM1-mediated increase in cytosolic calcium levels induced apoptosis through the ERK pathway.
Significance:
Melatonin induces mitochondrial apoptosis in osteoblasts by regulating the STIM1/cytosolic calcium elevation/ERK pathway. These basic findings provide a basis for further clinical studies on melatonin as a drug therapeutic for idiopathic scoliosis.
... MTNR1B polymorphism may lead to a down regulation of melatonin receptor 1B expression causing a clinical deficiency of the hormone 21 . Other studies have concluded that there is an abnormal melatonin-signaling pathway in the osteoblasts of AIS patients 22 and that the application of the melatonin antagonist of Luzindole and the calmodulin antagonist of Tamoxifen can improve the success rate of scoliosis in a bipedal rat model 23,24 . However, human melatonin levels are not consistent in different populations and melatonin deficiency as an etiological factor of scoliosis cannot be supported 17 . ...
... Melatonin deficiency has been implicated in AIS pathogenesis [135,13�]. However, subsequent studies did not agree with the theory that melatonin deficiency is a primary cause of AIS [137][138][139]. More recent trials, however, show that patients with severe AIS have dysfunctional melatonin signaling [118, 119,140]. ...
... Melatonin deficiency has been implicated in AIS pathogenesis [135,13�]. However, subsequent studies did not agree with the theory that melatonin deficiency is a primary cause of AIS [137][138][139]. More recent trials, however, show that patients with severe AIS have dysfunctional melatonin signaling [118, 119,140]. ...
Several theories have been proposed to explain the etiology of adolescent idiopathic scoliosis (AIS) until present. However, limited data are available regarding the impact of vitamin D insufficiency or deficiency on scoliosis. Previous studies have shown that vitamin D deficiency and insufficiency are prevalent in adolescents, including AIS patients. A series of studies conducted in Hong Kong have shown that as many as 30% of these patients have osteopenia. The 25-hydroxyvitamin D3 level has been found to positively correlate with bone mineral density (BMD) in healthy adolescents and negatively with Cobb angle in AIS patients; therefore, vitamin D deficiency is believed to play a role in AIS pathogenesis. This study attempts to review the relevant literature on AIS etiology to examine the association of vitamin D and various current theories. Our review suggested that vitamin D deficiency is associated with several current etiological theories of AIS. We postulate that vitamin D deficiency and/or insufficiency affects AIS development by its effect on the regulation of fibrosis, postural control, and BMD. Subclinical deficiency of vitamin K2, a fat-soluble vitamin, is also prevalent in adolescents; therefore, it is possible that the high prevalence of vitamin D deficiency is related to decreased fat intake. Further studies are required to elucidate the possible role of vitamin D in the pathogenesis and clinical management of AIS.
