Circular RNA circANAPC2 mediates the impairment of endochondral ossification by miR-874-3p/SMAD3 signalling pathway in idiopathic short stature.
Circular RNA circANAPC2 mediates the impairment of endochondral ossification by miR-874-3p/SMAD3 signalling pathway in idiopathic short stature.
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DOI：
10.1111/jcmm.16419
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发表时间：
2021-04
影响因子：
5.3
通讯作者：
Jia J
中科院分区：
文献类型：
--
作者：
Liu X;Du Z;Yi X;Sheng T;Yuan J;Jia J
特发性身材矮小是儿童身高偏低的主要原因。其确切的病因尚不清楚。最近的研究结果表明，外周血样本中circRNAs的异常表达与许多疾病有关。然而，迄今为止，circRNA异常表达在介导ISS发病机制中的作用在很大程度上仍然未知。通过circRNA微阵列分析和RT - qPCR鉴定了上调的circANAPC2。circANAPC2过表达抑制人软骨细胞增殖，细胞周期阻滞在G1期。circANAPC2过表达后，X型胶原、RUNX2、OCN和OPN的表达均显著下调。Von Kossa染色强度降低，碱性磷酸酶活性降低。荧光素酶报告基因分析结果显示circANAPC2可以被miR‐874‐3p靶向。CircANAPC2在人软骨细胞中的过表达抑制miR - 874 - 3p的表达。circANAPC2和miR - 874 - 3p的共定位通过原位杂交在人软骨细胞和小鼠股骨生长板中得到证实。拯救实验表明miR‐874‐3p高表达可拮抗circANAPC2过表达引起的软骨内成骨、肥大和软骨细胞生长的抑制。高通量筛选mRNA表达和RT - qPCR证实SMAD3在overcircANAPC2后表达差异最大。荧光素酶报告基因分析结果表明miR‐874‐3p可以被Smad3靶向，从而下调Smad3的表达。随后的SMAD3修复实验进一步证实，circANAPC2通过miR‐874‐3p/ SMAD3轴抑制软骨内成骨、肥大和软骨细胞生长。目前的研究提供证据表明circANAPC2可以作为ISS治疗的一个有希望的靶点。
Idiopathic short stature (ISS) is a main reason for low height among children. Its exact aetiology remains unclear. Recent findings have suggested that the aberrant expression of circRNAs in peripheral blood samples is associated with many diseases. However, to date, the role of aberrant circRNA expression in mediating ISS pathogenesis remains largely unknown. The up‐regulated circANAPC2 was identified by circRNA microarray analysis and RT‐qPCR. Overexpression of circANAPC2 inhibited the proliferation of human chondrocytes, and cell cycle was arrested in G1 phase. The expressions of collagen type X, RUNX2, OCN and OPN were significantly down‐regulated following circANAPC2 overexpression. Moreover, Von Kossa staining intensity and alkaline phosphatase activity were also decreased. Luciferase reporter assay results showed that circANAPC2 could be targeted by miR‐874‐3p. CircANAPC2 overexpression in human chondrocytes inhibits the expression of miR‐874‐3p. The co‐localization of circANAPC2 and miR‐874‐3p was confirmed in both human chondrocytes and murine femoral growth plates via in situ hybridization. The rescue experiment demonstrated that the high expression of miR‐874‐3p overexpression antagonized the suppression of endochondral ossification, hypertrophy and chondrocyte growth caused by circANAPC2 overexpression. A high‐throughput screening of mRNA expression and RT‐qPCR verified SMAD3 demonstrated the highest different expressions following overcircANAPC2. Luciferase reporter assay results indicated that miR‐874‐3p could be targeted by Smad3, thus down‐regulating the expression of Smad3. Subsequent rescue experiments of SMAD3 further confirmed that circANAPC2 suppresses endochondral ossification, hypertrophy and chondrocyte growth through miR‐874‐3p/Smad3 axis. The present study provides evidence that circANAPC2 can serve as a promising target for ISS treatment.
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