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Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14.
J Mol Med (Berl). 2016 Apr; 94(4):457-68.JM

Abstract

Accumulating evidence suggests that microRNAs (miRNAs) play an important role in intervertebral disc degeneration (IDD), but the precise role of specific miRNAs involved in this disease remains elusive. The purpose of this study was to identify IDD-specific miRNAs, followed by functional validation of results. MiRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing Solexa sequencing and quantitative real-time PCR (qRT-PCR). Biological functions of differential expression miRNAs were further investigated in vitro and in vivo. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 28 miRNAs that were differentially expressed in patients compared with controls. Following qRT-PCR confirmation, miR-193a-3p was significantly down-regulated in degenerative NP tissues. Moreover, its level was correlated with grade of disc degeneration. Through gain- and loss-of-function studies, miR-193a-3p was demonstrated to significantly promote type II collagen expression in NP cells. Knockdown of MMP14 induced effects on NP cells similar to those induced by miR-193a-3p. Bioinformatics target prediction identified MMP14 as a putative target of miR-193a-3p. Furthermore, luciferase reporter assays and Western blotting demonstrated that miR-193a-3p directly targets MMP14. MiR-193a-3p inhibited IDD in vitro and in vivo. The downregulation of miR-193a-3p induces the expression of MMP14, which promotes loss of type II collagen and thereby contributes to the development of human IDD. Our findings extend the role of miR-193a-3p in the pathogenesis of IDD and provide a potential novel therapeutic target for degenerative disc disease.

KEY MESSAGES

Intervertebral disc degeneration (ICC)-specific miRNA profile generated by next generation sequencing. Downregulation of miR-193a-3p promoted loss of type II collagen by directly targeting MMP14 in IDD. miR-193a-3p inhibited IDD in vitro and in vivo. miR-193a-3p may be a promising candidate for prevention of degenerative disc disease.

Authors+Show Affiliations

Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China.Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China.Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing, China.Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China.Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China.Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China.Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China.Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao road 87, Nanjing, 210009, China. wangchenor@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26620678

Citation

Ji, Ming-Liang, et al. "Downregulation of microRNA-193a-3p Is Involved in Invertebral Disc Degeneration By Targeting MMP14." Journal of Molecular Medicine (Berlin, Germany), vol. 94, no. 4, 2016, pp. 457-68.
Ji ML, Zhang XJ, Shi PL, et al. Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14. J Mol Med. 2016;94(4):457-68.
Ji, M. L., Zhang, X. J., Shi, P. L., Lu, J., Wang, S. Z., Chang, Q., Chen, H., & Wang, C. (2016). Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14. Journal of Molecular Medicine (Berlin, Germany), 94(4), 457-68. https://doi.org/10.1007/s00109-015-1371-2
Ji ML, et al. Downregulation of microRNA-193a-3p Is Involved in Invertebral Disc Degeneration By Targeting MMP14. J Mol Med. 2016;94(4):457-68. PubMed PMID: 26620678.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14. AU - Ji,Ming-Liang, AU - Zhang,Xue-Jun, AU - Shi,Pei-Liang, AU - Lu,Jun, AU - Wang,Shan-Zheng, AU - Chang,Qing, AU - Chen,Hui, AU - Wang,Chen, Y1 - 2015/12/01/ PY - 2015/07/29/received PY - 2015/11/17/accepted PY - 2015/11/08/revised PY - 2015/12/2/entrez PY - 2015/12/2/pubmed PY - 2016/12/27/medline KW - Intervertebral disc degeneration KW - MMP14 KW - miR-193a-3p KW - microRNAs SP - 457 EP - 68 JF - Journal of molecular medicine (Berlin, Germany) JO - J. Mol. Med. VL - 94 IS - 4 N2 - UNLABELLED: Accumulating evidence suggests that microRNAs (miRNAs) play an important role in intervertebral disc degeneration (IDD), but the precise role of specific miRNAs involved in this disease remains elusive. The purpose of this study was to identify IDD-specific miRNAs, followed by functional validation of results. MiRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing Solexa sequencing and quantitative real-time PCR (qRT-PCR). Biological functions of differential expression miRNAs were further investigated in vitro and in vivo. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 28 miRNAs that were differentially expressed in patients compared with controls. Following qRT-PCR confirmation, miR-193a-3p was significantly down-regulated in degenerative NP tissues. Moreover, its level was correlated with grade of disc degeneration. Through gain- and loss-of-function studies, miR-193a-3p was demonstrated to significantly promote type II collagen expression in NP cells. Knockdown of MMP14 induced effects on NP cells similar to those induced by miR-193a-3p. Bioinformatics target prediction identified MMP14 as a putative target of miR-193a-3p. Furthermore, luciferase reporter assays and Western blotting demonstrated that miR-193a-3p directly targets MMP14. MiR-193a-3p inhibited IDD in vitro and in vivo. The downregulation of miR-193a-3p induces the expression of MMP14, which promotes loss of type II collagen and thereby contributes to the development of human IDD. Our findings extend the role of miR-193a-3p in the pathogenesis of IDD and provide a potential novel therapeutic target for degenerative disc disease. KEY MESSAGES: Intervertebral disc degeneration (ICC)-specific miRNA profile generated by next generation sequencing. Downregulation of miR-193a-3p promoted loss of type II collagen by directly targeting MMP14 in IDD. miR-193a-3p inhibited IDD in vitro and in vivo. miR-193a-3p may be a promising candidate for prevention of degenerative disc disease. SN - 1432-1440 UR - https://www.unboundmedicine.com/medline/citation/26620678/Downregulation_of_microRNA_193a_3p_is_involved_in_invertebral_disc_degeneration_by_targeting_MMP14_ L2 - https://dx.doi.org/10.1007/s00109-015-1371-2 DB - PRIME DP - Unbound Medicine ER -