FOXO3-activated HOTTIP Sequesters MiR-615-3p Away from COL2A1 to Mitigate Intervertebral Disc Degeneration

Am J Pathol. 2023 Nov 17:S0002-9440(23)00421-2. doi: 10.1016/j.ajpath.2023.10.011. Online ahead of print.ABSTRACTKnockout of FOXO3 was found to impair IVD maturation and homeostasis in postnatal mice as well as facilitating extracellular matrix (ECM) degradation. RNA sequencing can uncover disease-related gene expression and investigate disease pathophysiology. High-throughput transcriptome sequencing and experimental validations were used to identify the essential gene and mechanism involved in intervertebral disc degeneration (IDD). Nucleus pulposus (NP) tissue samples were collected from the mice with conditional knockout of FOXO3 (FOXO3 KO) for high-throughput sequencing, followed by screening of differentially expressed lncRNAs and mRNAs. The mRNAs were subjected to GO and KEGG enrichment analyses. Interactions among FOXO3, HOTTIP, miR-615-3p and COL2A1 were analyzed. NP cells were subjected to a series of mimics, inhibitors, overexpression plasmids and shRNAs to validate the mechanisms of FOXO3 in controlling of HOTTIP/miR-615-3p/COL2A1 in IDD. Mechanistically, FOXO3 transcriptionally activated HOTTIP, facilitated the competitive HOTTIP binding to miR-615-3p and increased the expression of the miR-615-3p target gene COL2A1. Thus, NP cell proliferation was induced, cell apoptosis was diminished, resulting in delayed development of IDD. Conclusively, the transcription factor FOXO3 may decrease miR-615-3p binding to COL2A1 and upregulate COL2A1 expression by activating HOT...

Source: Am J Pathol - November 19, 2023 Category: Pathology Authors: Yingjie Hao Guangduo Zhu Lei Yu Zhinan Ren Weiwei Zhou Panke Zhang Xu Lian Source Type: research