Upregulated miR-224-5p suppresses osteoblast differentiation by increasing the expression of Pai-1 in the lumbar spine o
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Upregulated miR‑224‑5p suppresses osteoblast differentiation by increasing the expression of Pai‑1 in the lumbar spine of a rat model of congenital kyphoscoliosis Sho Ishiwata1,2 · Haku Iizuka1,3 · Hiroyuki Sonoda1,4 · Daisuke Tsunoda1 · Yuki Tajika5 · Hirotaka Chikuda1 · Noriyuki Koibuchi2 · Noriaki Shimokawa2,6 Received: 6 May 2020 / Accepted: 26 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Congenital scoliosis is defined by the presence of structural anatomical malformations that arise from failures of vertebral formation or segmentation before and after birth. The understanding of genetic background and key genes for congenital scoliosis is still poor. We herein report that the excess expression of plasminogen activator inhibitor-1 (Pai-1) induced by the upregulation of miR-224-5p is involved in the pathogenesis of congenital kyphoscoliosis through impaired osteoblast differentiation. We first investigated the variety and progression of abnormalities of the lumbar spines in Ishibashi (IS) rats, a rat model of congenital kyphoscoliosis. The rats had already shown fusion and division of the primary ossification center at postnatal day 4. Over time, the rats showed various abnormalities of the lumbar spine, including the fusion of the annular epiphyseal nucleus. At postnatal day 42, spinal curvature was clearly observed due to the fusion of the vertebral bodies. Using a microRNA array, we found that the expression of miR-224-5p was increased in the lumbar spine of the rats at postnatal day 4. The expression of Pai-1, which is involved in osteoblast differentiation regulated by miR-224-5p, was also increased, while the levels of type I collagen, a marker of osteoblast differentiation, were decreased in the lumbar spine. These results indicate that the aberrant expression of miRNA-224-5p and its target genes is involved in the impaired osteoblast differentiation and may provide a partial molecular explanation for the pathogenesis of congenital scoliosis. Keywords Congenital scoliosis · Kyphoscoliosis model rats · microRNA array · miR-224-5p · Plasminogen activator inhibitor-1 · Osteoblast differentiation
Introduction
* Noriaki Shimokawa shimokawa‑n@takasaki‑u.ac.jp 1
Department of Orthopedic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
2
Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
3
Isesaki Municipal Hospital, Isesaki, Japan
4
Japanese Red Cross Maebashi Hospital, Maebashi, Japan
5
Department of Anatomy, Gunma University Graduate School of Medicine, Gunma, Japan
6
Department of Nutrition, Takasaki University of Health and Welfare, 31‑1 Nakaorui‑machi, Takasaki, Gunma 370‑0033, Japan
Congenital scoliosis is a genetic disease characterized by the congenital malformation of the spinal vertebrae and is classified into formation failure, segmentation failure and mixed type [1]. The symptoms depend on the morphology of the vertebral malformation and the type o
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