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

Zhaoyang Liu,Janani Ramachandran,Ryan S Gray,Steven A Vokes

doi:10.1242/dmm.041251

Zhaoyang Liu, Janani Ramachandran + Show 2 more

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https://doi.org/10.1242/dmm.041251

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Journal: Disease Models & Mechanisms	Publication Date: Dec 1, 2019
Citations: 16	License type: CC BY 4.0

Affiliation: The University of Texas at Austin

Abstract

ABSTRACTIdiopathic 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.

Highlights

Idiopathic scoliosis (IS) is the most common pediatric spinal deformity characterized by a lateral curvature of the spine >10°, affecting ~3% of children worldwide (Wise et al, 2008)
Our results demonstrate that protein arginine methyltransferase 5 (PRMT5) regulates terminal hypertrophic differentiation through positive regulation of RUNX2 and matrix metalloproteinase 13 (Mmp13) expression and by negative regulation of Indian hedgehog (Ihh) expression during perinatal development, resulting in an obvious delay of terminal hypertrophic chondrocyte differentiation
We suggest this is in part due to the loss of RUNX2 and Mmp13 expression which promote terminal hypertrophic chondrocyte differentiation as well as, due to increased, ectopic Ihh expression may act to counter hypertrophic differentiation

Summary

Introduction

Idiopathic scoliosis (IS) is the most common pediatric spinal deformity characterized by a lateral curvature of the spine >10°, affecting ~3% of children worldwide (Wise et al, 2008). Large-scale genome wide association studies implicated several candidate loci associated with IS, including associations with GPR126 (ADGRG6), LBX1, CHL1 and SOX9 genes (Ikegawa, 2016; Kou et al, 2013; Sharma et al, 2011; Takahashi et al, 2011) Some of these candidate genes associated with IS and their effectors, including Adgrg6/Gpr126 (Karner et al, 2015), Sox (Henry et al, 2012), Shp (Kim et al, 2013), Gdf5/6 (Settle et al, 2003), and Fgf (Gao et al, 2015), are known to develop spine defects and scoliosis when mutated in mouse. 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)

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