Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

Abstract

Pathological changes in the ligamentum flavum (LF) can be defined as a process of chronic progressive aberrations in the nature and structure of ligamentous tissues characterized by increased thickness, reduced elasticity, local calcification, or aggravated ossification, which may cause severe myelopathy, radiculopathy, or both. Hypertrophy of ligamentum flavum (HLF) and ossification of ligamentum flavum (OLF) are clinically common entities. Though accumulated evidence has indicated both genetic and environmental factors could contribute to the initiation and progression of HLF/OLF, the definite pathogenesis remains fully unclear. MicroRNAs (miRNAs), one of the important epigenetic modifications, are short single-stranded RNA molecules that regulate protein-coding gene expression at posttranscriptional level, which can disclose the mechanism underlying diseases, identify valuable biomarkers, and explore potential therapeutic targets. Considering that miRNAs play a central role in regulating gene expression, we summarized current studies from the point of view of miRNA-related molecular regulation networks in HLF/OLF. Exploratory studies revealed a variety of miRNA expression profiles and identified a battery of upregulated and downregulated miRNAs in OLF/HLF patients through microarray datasets or transcriptome sequencing. Experimental studies validated the roles of specific miRNAs (e.g., miR-132-3p, miR-199b-5p in OLF, miR-155, and miR-21 in HLF) in regulating fibrosis or osteogenesis differentiation of LF cells and related target genes or molecular signaling pathways. Finally, we discussed the perspectives and challenges of miRNA-based molecular mechanism, diagnostic biomarkers, and therapeutic targets of HLF/OLF.

TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

“…Emerging evidence has demonstrated that dysregulated miRNAs is involved in the occurrence and progression of HLF [ 22 , 43 ]. Yu et al identified that miR-221 was down-regulated in HLF tissues, and overexpressing miR-221 inhibited the expression of collagens I and collagens III by sponging TIMP-2, thus inhibiting HLF formation [ 36 ].…”

“…There is currently no particularly effective conservative treatment to delay or reverse the HLF-induced LSCS except surgical decompression. Surgical removal of the hypertrophic ligamentum flavum can achieve spinal decompression, but not only the risks and postoperative complications of surgery are particularly prominent but also many patients with underlying diseases (such as diabetes, hypertension and hyperlipidemia) are intolerant to surgery [ 21 , 37 , 43 ]. Although fibrosis have been proved to be the key pathological feature of HLF, the precise mechanism of the pathology of LF fibrosis has not been fully elucidated [ 32 ].…”

“…MiRNAs is a class of non-coding single-stranded RNA molecules with a length of about 19–25 nucleotides encoded by endogenous genes, which participate in the regulation of post-transcriptional gene expression in plants and animals [ 19 ]. Current studies have been demonstrated that dysregulated miRNAs play an important role in the pathogenesis of HLF [ 43 ]. For example, Li P et al have demonstrated that miR-10396-3p is significantly decreased in the mechanical stress (MS)-induced HLF and overexpressing miR-10396-3p inhibits MS-induced HLF by targeting the inhibition expression of IL-11 [ 17 ].…”

Deciphering Obesity-Related Gene Clusters Unearths SOCS3 Immune Infiltrates and 5mC/m6A Modifiers in Ossification of Ligamentum Flavum Pathogenesis

“…According to the inclusion criteria ( 1 ): organism: Homo sapiens ( 2 ); expression profiling by microarray; and ( 3 ) samples: OLF ligament tissues and normal ligament tissues, an eligible high-throughput RNA-sequencing data (GSE106253) was downloaded from GEO for further analysis. The microarray data contains the mRNA information of ligamentum flavum tissue from 4 OLF patients and 4 healthy individuals.…”

“…Ossification of ligamentum flavum (OLF) is the major pathogeny of severe thoracic myelopathy characterized by abnormally heterotopic bone formation of the intraspinal ligament with unelucidated pathogenesis ( 1 ). To date, genetic, mechanical stress, degeneration, inflammatory, and metabolic factors have been found to be involved in the occurrence and progression of OLF ( 2 – 6 ).…”