Circular RNA PDK1 targets miR‐4731‐5p to enhance TNXB expression in ligamentum flavum hypertrophy. Issue 5 (4th April 2023)

• Record Type: Journal Article
• Authors: Zhang, Kai; Wang, Xin; Zeng, Li‐Ting; Yang, Xiao; Cheng, Xiao‐Fei; Tian, Hai‐Jun; Chen, Chen; Sun, Xiao‐Jiang; Zhao, Chang‐Qing; Ma, Hui; Zhao, Jie
• Is Part Of: FASEB journal. Volume 37:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-04-04
• Subjects: circPDK1 -- ligamentum flavum hypertrophy -- lumbar spinal stenosis -- miR‐4731‐5p -- TNXB; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202200022RR
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR‐4731 and miR‐4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound‐healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis‐related protein (alpha smooth muscle actin (α‐SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase‐2 (MMP‐2) and TNXB) in LF whereas miR‐4731‐5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR‐4731‐5p. Co‐overexpression of miR‐4731‐5p partially reversed the proliferative and fibrosis‐prompting effects of circPDK1 or TNXB. The circPDK1‐miR‐4731‐TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in‐depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy‐induced LSS. Abstract : circPDK1‐miR‐4731‐TNXB pathway is a regulatory axis in ligamentum flavum (LF) hypertrophy. circPDK1 negatively regulates miR‐4731 to increase the expression levels of TNXB that controls the expression of fibrosis‐related protein (α‐SMA, LOXL2, Collagen I, and MMP‐2), thereby promoting the proliferation, migration, and fibrosis of LF cells, which leads to LF hypertrophy.