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Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.

ABSTRACT: The etiopathogenesis of idiopathic scoliosis (IS), a highly prevalent spinal deformity that occurs in the absence of obvious congenital or physiological abnormalities, is poorly understood. Although recent zebrafish genetic studies have linked cilia motility and cerebrospinal fluid (CSF) flow defects with scoliosis progression, underlying mechanisms were not identified. Here, we use next-generation sequencing and conditional genetic methodologies to define the spatial and biological origins of spinal curve formation in ptk7 mutant zebrafish, a faithful IS model. We demonstrate that focal activation of proinflammatory signals within the spinal cord is associated with, and sufficient for, induction of spinal curvatures. Furthermore, administration of acetylsalicylic acid (aspirin) or N-acetylcysteine (NAC) to juvenile ptk7 mutants significantly reduces the incidence and/or severity of scoliosis phenotypes. Together, our results implicate neuroinflammation, downstream of CSF defects, in spinal curve formation and provide intriguing evidence that simple immunomodulating therapies might prove effective in managing idiopathic-like spinal deformities.

SUBMITTER: Van Gennip JLM

PROVIDER: S-EPMC6291318 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.

Van Gennip J L M JLM Boswell C W CW Ciruna B B

Science advances 20181212 12

The etiopathogenesis of idiopathic scoliosis (IS), a highly prevalent spinal deformity that occurs in the absence of obvious congenital or physiological abnormalities, is poorly understood. Although recent zebrafish genetic studies have linked cilia motility and cerebrospinal fluid (CSF) flow defects with scoliosis progression, underlying mechanisms were not identified. Here, we use next-generation sequencing and conditional genetic methodologies to define the spatial and biological origins of s ...[more]

PMID: 30547092

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Project description:There is no consensus on the definition of a structural proximal thoracic curve (PTC) and the indications for fusion. As such, we assessed a single institute's experience in the management of large PTCs (>35 degrees) in patients with adolescent idiopathic scoliosis (AIS) who were either fused or not fused. A retrospective radiographic analyses of 30 consecutive AIS patients with double thoracic curves who underwent PSF with a minimum of 2 years' follow-up were included for review. The patients were divided into two groups: group 1 (n = 15 patients) with fusion extended up to T2 or T3 and group 2 (n = 15) with fusion limited to T5 or below. Shoulder balance was assessed according to clavicular angle, first-rib difference, and radiographic shoulder height difference (SHD). PTCs were defined based on a Cobb angle of >35, the presence of apical rotation, and a positive T1 tilt. The decision to fuse the PTC was based on curve magnitude only, with those between 35 and 45 degrees undergoing a selective fusion of the main thoracic curve (MTC), with both curves fused if the PTC was more than 45 degrees. In group 1, there were eight females and seven males. Their ages ranged between 12 and 33 years, with a mean of 16.2 ± 5.5 years. Postoperatively, the mean PTC correction was 45.6%, which statistically differed from preoperative status (p = 0.001). No statistical difference was noted in T1 tilt and the first-rib difference from preoperative to postoperative follow-up (p > 0.05). However, the clavicular angle and SHD were increased significantly at the immediate postoperative interval (p < 0.05) but demonstrated no significant changes between the initial and the last follow-up values (p > 0.05). Group 2 consisted of one male and 14 females. The mean age was 16.4 ± 4 years (range: 11 to 28 years). The mean spontaneous PTC correction was 28.3% and remained essentially unchanged at the end of the follow-up. The improvement in the curve from preoperative status was highly statistically significant (p = 0.001). All radiographic shoulder parameters exhibited a significant increase in the immediate postoperative period and at last follow-up, and shoulder balance improvement was not noted on follow-up. Although both groups were not statistically similar with regards to the preoperative PTC, AVR, apical vertebral translation, and shoulder parameters, no significant difference could be found in PTC or shoulder parameters between both groups at last follow-up (p > 0.05). Our study illustrates important observations that should be considered in defining the PTC for fusion consideration. Spontaneous correction of the PTC occurs in structural curves greater than 35 degrees and less than 45 degrees, and this correction is maintained over time. Despite that correction, radiographic shoulder parameters are expected to slightly increase. Nonfusion strategy may be appropriate for PTCs between 35 and 45 degrees. After fusion of both the MTC and the PTC, the radiographic shoulder parameters did not significantly differ. Preoperative radiographic shoulder parameters are not predictive of postoperative shoulder imbalance.

Dataset Information

Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.

Publications

Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.

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