Unique local bone tissue characteristics in iliac crest bone biopsy from adolescent idiopathic scoliosis with severe spinal deformity

Wang, Zhiwei; Chen, Huanxiong; Yu, Yan; Zhang, Jiajun; Cheuk, Ka Yee; Ng, Bobby Kin Wah; Qiu, Yong; Guo, Xia; Cheng, Jack C. Y.; Lee, Wayne

doi:10.1038/srep40265

Cited by 19 publications

(14 citation statements)

References 60 publications

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“…Several pathways leading to RUNX2 activation, such as BMP, bFGF and IGF, were found to converge at the MAPK cascade 32,49,50 . Moreover, several recent studies demonstrated that there are positive correlations between low RUNX2 expression and BMD in AIS patients 51,52 . These studies are consistent with our results, suggesting that MAPK signalling plays a key role in bone formation and may be implicated in AIS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells

Li¹,

Li²,

Chen³

et al. 2019

Cell Death Dis

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Adolescent idiopathic scoliosis (AIS) is a complex, three-dimensional deformity of the spine that commonly occurs in pubescent girls. Decreased osteogenic differentiation and aberrant melatonin signalling have been demonstrated in mesenchymal stem cells (MSCs) from AIS patients and are implicated in the pathogenesis of AIS. However, the molecular mechanisms underlying these abnormal cellular features remain largely unknown. Our previous work comparing gene expression profiles between MSCs from AIS patients and healthy controls identified 1027 differentially expressed genes. In the present study, we focused on one of the most downregulated genes, SPRY4, in the MAPK signalling pathway and examined its role in osteogenic differentiation. We found that SPRY4 is markedly downregulated in AIS MSCs. Knockdown of SPRY4 impaired differentiation of healthy MSCs to osteoblasts, while SPRY4 overexpression in AIS MSCs enhanced osteogenic differentiation. Furthermore, melatonin treatment boosted osteogenic differentiation, whereas SPRY4 ablation ablated the promotional effects of melatonin. Moreover, SPRY4 was upregulated by melatonin exposure and contributed to osteogenic differentiation and melatonin response in a MEK-ERK1/2 dependent manner. Thus, loss of SPRY4 in bone marrow derived-MSCs results in reduced osteogenic differentiation, and these defects are further aggravated under the influence of melatonin. Our findings provide new insights for understanding the role of melatonin in AIS aetiology and highlight the importance of MSCs in AIS pathogenesis.

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Section: Discussionmentioning

confidence: 99%

SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells

Li¹,

Li²,

Chen³

et al. 2019

Cell Death Dis

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“…Our recent study firstly revealed a causative relationship between aberrant microRNA-145À5p (miR-145) expression and abnormal osteocyte structure and function in AIS [20]. The miR-145 expression inhibited osteocyte dendritic formation and function by disturbing active b-catenin expression and its transcriptional activity [18]. We also reported negative correlation between plasma miR-145 and serum levels of bone metabolic markers [18].…”

Section: Introductionmentioning

confidence: 92%

“…The root cause of low bone mass in AIS is unclear. Bone histomorphometry studies on bone biopsies from surgical cases indicated abnormally higher bone turnover in AIS [18,19]. It is speculated that an abnormality of bone metabolism in AIS possibly results in the spine being more vulnerable to deformity.…”

Section: Introductionmentioning

confidence: 99%

A validated composite model to predict risk of curve progression in adolescent idiopathic scoliosis

Zhang

Cheuk

et al. 2020

eClinicalMedicine

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Background: In adolescent idiopathic scoliosis (AIS), the continuous search for effective prognostication of significant curve progression at the initial clinical consultation to inform decision for timely treatment and to avoid unnecessary overtreatment remains a big challenge as evidence of the multifactorial etiopathogenic nature is increasingly reported. This study aimed to formulate a composite model composed of clinical parameters and circulating markers in the prediction of curve progression. Method: This is a two-phase study consisting of an exploration cohort (120 AIS, mean Cobb angle of 25° § 8.5 at their first clinical visit) and a validation cohort (51 AIS, mean Cobb angle of 23° § 5.0°at the first visit). Patients with AIS were followed-up for a minimum of six years to formulate a composite model for prediction. At the first visit, clinical parameters were collected from routine clinical practice, and circulating markers were assayed from blood. Finding: We constructed the composite predictive model for curve progression to severe Cobb angle > 40°w ith a high HR of 27.9 (95% CI of 6.55 to 119.16). The area under curve of the composite model is higher than that of individual parameters used in current clinical practice. The model was validated by an independent cohort and achieved a sensitivity of 72.7% and a specificity of 90%. Interpretation: This is the first study proposing and validating a prognostic composite model consisting of clinical and circulating parameters which could quantitatively evaluate the probability of curve progression to a severe curvature in AIS at the initial consultation. Further validation in clinic will facilitate application of composite model in assisting objective clinical decision.

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“…A compromised mechanical competence alongside low BMD also increases fracture risk and can be an underlying cause of scoliosis. (65)(66)(67) Unfortunately, natural history BMD data of CS patients throughout early development is not available, to the best of our knowledge.…”

Section: Abnormal Vertebrae and Vbmd Variabilitymentioning

confidence: 99%

Abnormal craniofacial and spinal bone development withcol2a1a depletion in a zebrafish model of CHARGE syndrome

Breuer¹,

Rummler

Zaouter³

et al. 2020

Preprint

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CHARGE syndrome patients present features of idiopathic scoliosis in over 60% of cases, reduced bone mineral density and in a few cases osteopenia. While several clinical cases and studies regarding the spinal deformities in CHARGE syndrome bearing CHD7 mutations are well-documented, the underlying mechanisms remain elusive. Here, we detect and quantitatively analyze skeletal abnormalities in adult and young chd7-/- larvae. We show that young chd7-/- larvae present with scoliosis and kyphosis already at 9 dpf. Gene expression analysis confirmed the reduction of osteoblast markers and Pparγ targets. MicroCT analyses identified abnormal Weberian apparatus structure and vertebral body morphology in chd7-/- mutants, with highly mineralized inclusions, along with variances in bone mineral density and bone volume. Additionally, we detect a specific depletion of Col2a1a in the zebrafish vertebral cartilage, in line with a significantly reduced number of chondrocytes. Our study is the first to elucidate the mechanisms underlying morphological changes in vertebrae of adult chd7-/- zebrafish and decreased spinal integrity. The chd7-/- zebrafish will be beneficial in future investigations of the underlying pathways of spinal deformities in CHARGE syndrome.

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Unique local bone tissue characteristics in iliac crest bone biopsy from adolescent idiopathic scoliosis with severe spinal deformity

Cited by 19 publications

References 60 publications

SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells

SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells

A validated composite model to predict risk of curve progression in adolescent idiopathic scoliosis

Abnormal craniofacial and spinal bone development withcol2a1a depletion in a zebrafish model of CHARGE syndrome

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