Animal Models of Idiopathic Scoliosis

Liu, Zhaoyang; Gray, Ryan S.

doi:10.1007/978-3-319-90149-7_5

Cited by 8 publications

(10 citation statements)

References 134 publications

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“…Our current studies suggest that the cartilaginous tissues play a prominent role in the pathogenesis of infantile IS. In agreement, genetic defects in osteochondral progenitors of the spine inducing IS in mice also occurs in other genetic mouse models displaying IS (Liu and Gray, 2018), including conditional mutant mice of the Gpr126/Adgrg6 (Karner et al, 2015), Sox9 (Henry et al, 2012), and Gdf5/6 (Settle et al, 2003) genes. These findings underscore the importance of proper cartilage maturation, including endochondral ossification, for maintaining spine stability during maturation and development of the spine.…”

Section: Asymmetrical Properties Of the Spine Results In Scoliosismentioning

confidence: 54%

“…The molecular genetics and underlying pathology of IS are largely unknown, more so for infantile onset forms of the disease. Asymmetries of the vertebral body growth and of the mechanical properties of the bony prominences, cartilaginous joints of the vertebral bodies, and musculature attachments of the spinal column have long been hypothesized to underlie the formation of idiopathic scoliosis (Liu and Gray, 2018). Our results suggest that the onset of infantile IS in Col2Cre;Prmt5 f/f mutant mice is the result of obvious defects in endochondral ossification of the spine.…”

Section: Asymmetrical Properties Of the Spine Results In Scoliosismentioning

confidence: 59%

“…Some of these candidate genes associated with IS and their effectors, including Adgrg6/Gpr126 (Karner et al, 2015), Sox9 (Henry et al, 2012), Shp2 (Kim et al, 2013), Gdf5/6 (Settle et al, 2003), and Fgf3 (Gao et al, 2015), are known to develop spine defects and scoliosis when mutated in mouse. Interestingly, a majority of these genes are involved with the development and homeostasis of connective tissues and cartilages, indicating a potential link between cartilaginous tissues and the pathogenesis of IS (Liu and Gray, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of terminal hypertrophic chondrocyte differentiation inPrmt5mutant mice modeling infantile idiopathic scoliosis

Ramachandran

Vokes

Gray

2019

Preprint

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Idiopathic scoliosis (IS) is the most common type of musculoskeletal defect effecting children and is classified by age of onset, location, and degree of spine curvature. Although rare, the onset of IS during infancy is the more severe and rapidly progressive form of the disease, leading to increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remain elusive. Here, we show that PRMT5 is critical for the regulation of terminal hypertrophic chondrocyte differentiation in the spine and models infantile IS in mouse. Conditional ablation of PRMT5 in osteochondral progenitors led to impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of several markers of endochondral ossification revealed increased COLX and Ihh expression and a dramatic reduction of Mmp13 and RUNX2 expression in the intervertebral disc and vertebral growth plate. Furthermore, we demonstrate that PRMT5 function in committed chondrogenic lineages is required for regulation of COLX expression in the adult spine. Together, our results establish PRMT5 as a critical regulator of hypertrophic chondrocyte differentiation and endochondral bone formation in spine development and maintenance.Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. and Karsenty, G. (1997). Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747-754. Dy, P., Wang, W., Bhattaram, P., Wang, Q., Wang, L., Ballock, R. T. and Lefebvre, V. (2012). Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell 22, 597-609. . AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblastspecific element 2/AP-1 composite element.

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Section: Asymmetrical Properties Of the Spine Results In Scoliosismentioning

confidence: 54%

Section: Asymmetrical Properties Of the Spine Results In Scoliosismentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of terminal hypertrophic chondrocyte differentiation inPrmt5mutant mice modeling infantile idiopathic scoliosis

Ramachandran

Vokes

Gray

2019

Preprint

Self Cite

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“…Functional studies informed by human genetic studies of IS using animal models show that defects in connective tissue and cartilaginous tissues of the spine underlie the pathogenesis of some forms of IS in humans (Karner et al, 2015;Kim et al, 2013). Asymmetries in vertebral body growth and in mechanical properties of the bony prominences, cartilaginous joints of the vertebral bodies and musculature attachments of the spinal column have long been hypothesized to underlie the formation of IS (Liu and Gray, 2018). Our demonstration of IS-like scoliosis during early perinatal development in Col2Cre;Prmt5 f/f mutant mice phenotypically models infantile-onset IS in humans.…”

Section: Asymmetrical Properties Of the Spine Results In Scoliosismentioning

confidence: 99%

“…Scoliosis is a common phenotype in mutant mouse models that disrupt genes involved with the development and homeostasis of cartilages and connective tissues, including Adgrg6/Gpr126 (Karner et al, 2015), Sox9 (Henry et al, 2012), Shp2 (Ptpn11) (Kim et al, 2013), Gdf5/6 (Settle et al, 2003) and Fgf3 (Gao et al, 2015). The convergence of human genetic data and mutant models of scoliosis in mouse is indicative of a potential relationship between the physiology of cartilaginous tissues of the spine and the pathogenesis of IS (Liu and Gray, 2018).…”

Section: Introductionmentioning

confidence: 99%

Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

Liu

Ramachandran

Vokes

et al. 2019

Disease Models &Amp; Mechanisms

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Idiopathic scoliosis (IS) is the most common type of musculoskeletal defect affecting children worldwide, and is classified by age of onset, location and degree of spine curvature. Although rare, IS with onset during infancy is the more severe and rapidly progressive form of the disease, associated with increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remains elusive. Here, we demonstrate the role of PRMT5 in the infantile IS phenotype in mouse. Conditional genetic ablation of PRMT5 in osteochondral progenitors results in impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of these several markers of endochondral ossification revealed increased type X collagen (COLX) and Ihh expression, coupled with a dramatic reduction in Mmp13 and RUNX2 expression, in the vertebral growth plate and in regions of the intervertebral disc in the Prmt5 conditional mutant mice. We also demonstrate that PRMT5 has a continuous role in the intervertebral disc and vertebral growth plate in adult mice. Altogether, our results establish PRMT5 as a critical promoter of terminal hypertrophic chondrocyte differentiation and endochondral bone formation during spine development and homeostasis. This article has an associated First Person interview with the first author of the paper.

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Genetic animal modeling for idiopathic scoliosis research: history and considerations

et al. 2022

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Animal Models of Idiopathic Scoliosis

Cited by 8 publications

References 134 publications

Regulation of terminal hypertrophic chondrocyte differentiation inPrmt5mutant mice modeling infantile idiopathic scoliosis

Regulation of terminal hypertrophic chondrocyte differentiation inPrmt5mutant mice modeling infantile idiopathic scoliosis

Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

Genetic animal modeling for idiopathic scoliosis research: history and considerations

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