Identification of Novel Genes in Osteoarthritic Fibroblast-Like Synoviocytes Using Next-Generation Sequencing and Bioinformatics Approaches

Abstract

Synovitis in osteoarthritis (OA) the consequence of low grade inflammatory process caused by cartilage breakdown products that stimulated the production of pro-inflammatory mediators by fibroblast-like synoviocytes (FLS). FLS participate in joint homeostasis and low grade inflammation in the joint microenvironment triggers FLS transformation. In the current study, we aimed to identify differentially expressed genes and potential miRNA regulations in human OA FLS through deep sequencing and bioinformatics approaches. The 245 differentially expressed genes in OA FLS were identified, and pathway analysis using various bioinformatics databases indicated their enrichment in functions related to altered extracellular matrix organization, cell adhesion and cellular movement. Moreover, among the 14 dysregulated genes with potential miRNA regulations identified, src kinase associated phosphoprotein 2 (SKAP2), adaptor related protein complex 1 sigma 2 subunit (AP1S2), PHD finger protein 21A (PHF21A), lipoma preferred partner (LPP), and transcription factor AP-2 alpha (TFAP2A) showed similar expression patterns in OA FLS and OA synovial tissue datasets in Gene Expression Omnibus database. Ingenuity Pathway Analysis identified the dysregulated LPP participated in cell migration and cell spreading of OA FLS, which was potentially regulated by miR-141-3p. The current findings suggested new perspectives into understanding the novel molecular signatures of FLS involved in the pathogenesis of OA, which may be potential therapeutic targets.

A Novel Intercellular Communication-Associated Gene Signature for Prognostic Prediction and Clinical Value in Patients With Lung Adenocarcinoma

“… Tanaka et al (2016) revealed that SKAP2 is related to tumor-associated macrophage infiltration and facilitates the metastatic progression of lung cancer in mise. The prognostic value of SKAP2 was also reported in previous studies using bioinformatics analyses ( Kuranami et al, 2015 ; Tanaka et al, 2016 ; Chen et al, 2019 ). Studies showed that CDH4 could be regulated by miR-211-5p to inhibit the proliferation, migration, and invasion of LUAD ( Zhang et al, 2020 ).…”

Organ- and Site-Specific HOX Gene Expression in Stromal Cells

“…Arthritic joints are characterized by rearrangements and dysregulated gene expression of bone, cartilage and synovial tissues [88,89]. The exact molecular and cellular events leading to the development of the different kinds of arthritis still remain elusive, but involvement of HOX gene regulation in the key tissues affected by rheumatic muscular-skeletal diseases indicate a potential link between arthritis development and HOX transcription factors.…”

MicroRNAs in Synovial Pathology Associated With Osteoarthritis

“…Considering FLS as essential participants in joint homeostasis and contributors to OA synovial pathology, it is not surprising that OA FLS show differential miRNA profiles. Recently, deep sequencing identified 245 differentially expressed genes in OA FLS and bioinformatics analyses highlighted “ECM organization and altered cellular movement” as one of the most enriched OA FLS functions connected to the differentially expressed genes and miRNA network ( 21 ). OA FLS also exhibit an independent miRNA signature from rheumatoid arthritis (RA) FLS, negatively correlating to the expression levels of their putative target genes ( 22 ).…”

“…Integrated analyses examining miRNA and transcript profiles in parallel will help elucidate dysregulated miRNA and RNA interactions occurring in OA. In OA, Chen et al performed RNA sequencing alongside small RNA sequencing in OA FLS compared to those derived from healthy tissue ( 21 ). Putative targets of dysregulated miRNAs were predicted by bioinformatic approaches, including 14 genes (11 upregulated and 3 downregulated) that require further biological validations ( 21 ).…”

“…In OA, Chen et al performed RNA sequencing alongside small RNA sequencing in OA FLS compared to those derived from healthy tissue ( 21 ). Putative targets of dysregulated miRNAs were predicted by bioinformatic approaches, including 14 genes (11 upregulated and 3 downregulated) that require further biological validations ( 21 ). Another study attempted to identify differential mRNA and miRNA expression in the DMM mouse OA model using microarray and RT-qPCR, but found no evidence of differential expression of miRNAs and RNAs levels between sham and DMM-induced OA mice at 1 or 6 weeks after surgery ( 23 ).…”