title: Regulation of insulin-like growth factor 1 receptor signaling by microRNA-4458 in the development of lumbar disc degeneration.
abstract: A potential role of Insulin-like growth factor 1 (IGF1) receptor/phosphatidylinositol-3 kinase (PI3k)/Akt signaling in the initiation and progression of Lumbar disc degeneration (LDD) has been recently reported. However, the regulation of IGF1 receptor (IGF1R) at post-transcriptional levels in the development of LDD remains unknown. Here, we studied the effects of microRNA-4458 on the expression of IGF1R. We examined the IGF1R levels and microRNA-4458 (miR-4458) levels in the resected LDD discs, compared with the traumatized, non-LDD discs. We analyzed the binding of miR-4458 to the 3'-UTR of IGF1R mRNA and its effects on IGF1R translation by bioinformatics analysis and by luciferase-reporter assay, respectively. We modified miR-4458 levels in a human nucleus pulposus SV40 cell line (HNPSV), and examined the effects of miR-4458 on the expression of IGF1R and Akt, as well as their phosphorylation. We found that the levels of miR-4458 were significantly higher and the levels of IGF1R were significantly lower in LDD discs, compared with the control non-LDD discs. The levels of IGF1R inversely correlated with the levels of miR-4458 in LDD discs. Moreover, miR-4458 was found to bind to the 3'-UTR of IGF1R mRNA to prevent its translation. In miR-4458-modified HNPSV cells, we found that miR-4458 decreased both total IGF1R and phosphorylated IGF1R, resulting in deceases in phosphorylated Akt. Thus, these data suggest that miR-4458 may suppress PI3k/Akt signaling pathway through 3'-UTR-inhibtion of IGF1R mRNA to promote development of LDD.
authors.affiliation: Department of Orthopedics, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University 1158 Gongyuan East Road, Shanghai 201700, China.
authors.forename: Zuo-Qing
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University 1158 Gongyuan East Road, Shanghai 201700, China.
authors.forename: Wen-Qin
authors.initials: WQ
authors.lastname: Fu
authors.affiliation: Department of Orthopedics, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University 1158 Gongyuan East Road, Shanghai 201700, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, The Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
keywords: Lumbar disc degeneration (LDD); insulin-like growth factor 1 (IGF1); insulin-like growth factor 1 receptor (IGF1R); miR-4458