Down-Regulation of microRNA-30d Alleviates Intervertebral Disc Degeneration Through the Promotion of FOXO3 and Suppressi
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ORIGINAL RESEARCH
Down‑Regulation of microRNA‑30d Alleviates Intervertebral Disc Degeneration Through the Promotion of FOXO3 and Suppression of CXCL10 Peng Xia1 · Xu Gao2 · Fang Li2 · Liwei Shao2 · Yifu Sun1 Received: 19 March 2020 / Accepted: 23 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract MicroRNAs (miRNAs/miRs) are important biomarkers for the progression of intervertebral disc degeneration (IDD). We investigated the role of miR-30d in IDD progression through its interactions with forkhead box O3 (FOXO3) and C-X-C motif ligand 10 (CXCL10). We first measured the expression of miR-30d, FOXO3, and CXCL10 in NP cells cultured from IDD patients. RNA-immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were then employed to test the relationship among miR-30d, FOXO3, and CXCL10. Besides, gain- and loss-of function approaches were performed to assess the functional roles of miR-30d and FOXO3 in IDD in vitro and in vivo. We found high expression of miR-30d and CXCL10 and low expression of FOXO3 in IDD. We showed that miR-30d specifically targeted FOXO3, and that down-regulation of miR-30d promoted proliferation and inhibited apoptosis of NP cells in IDD by increasing the expression of FOXO3. Besides, FOXO3 inhibited apoptosis of NP cells by downregulation of CXCL10 expression. Moreover, inhibition of miR-30d promoted proliferation and inhibited apoptosis of NP cells in IDD by decreasing CXCL10. Furthermore, findings in the mouse IDD model confirmed the inhibitory role of decreased miR-30d in IDD progression. Thus, we show that downregulation of miR-30d could promote the proliferation of NP cells by increasing FOXO3 and decreasing CXCL10 expression, which may provide a novel therapeutic target for IDD. Keywords MicroRNA-30d · Forkhead box O3 · C-X-C motif chemokine 10 · Intervertebral disc degeneration · Proliferation
Introduction Intervertebral disc degeneration (IDD) is one of the main reasons for chronic back pain, which causes a considerable socioeconomic burden from loss of job productivity [1]. IDD has a multifactorial aetiology that is influenced by many risk factors, including genetics as well as aging, injury, spine deformity and lifestyles (for example, smoking habits, engagement in physical activity, posture, and work-related injury) [2, 3]. Even though some biological approaches such * Yifu Sun [email protected] 1
Department of Orthopedics, Second Hospital of Jilin University, Changchun 132000, People’s Republic of China
Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, People’s Republic of China
2
as growth factor treatment or cell and gene therapies have been successful in improving IDD symptoms, there is no approach for targeting directly the underlying pathology [4]. Apoptosis of nucleus pulposus (NP) cells is one vital factor contributing to IDD, but the mechanisms triggering this phenomenon in IDD remain unclear [5]. Therefore, we attempt i
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