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Interleukin-17A causes osteoarthritis-like transcriptional changes in human osteoarthritis-derived chondrocytes and synovial fibroblasts in vitro

ABSTRACT: Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171952 | GEO | 2021/06/02

REPOSITORIES: GEO

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Systematic Analysis of Transcriptomic Profile of Chondrocytes in Osteoarthritis Using Next-Generation Sequencing and Bioinformatics

Project description:The phenotypic change of chondrocytes and the interplay between cartilage and subchondral bone in osteoarthritis (OA) has received much attention. Structural changes with nerve ingrowth and vascular penetration within OA cartilage may contribute to arthritic joint pain. The aim of this study was to identify differentially expressed genes and potential miRNA regulations in OA knee chondrocytes through next-generation sequencing and bioinformatics analysis. Results suggested the involvement of SMAD family member 3 (SMAD3) and Wnt family member 5A (WNT5A) in the growth of blood vessels and cell aggregation, representing features of cartilage damage in OA. Additionally, 26 dysregulated genes with potential miRNA⁻mRNA interactions were identified in OA knee chondrocytes. Myristoylated alanine rich protein kinase C substrate (MARCKS), epiregulin (EREG), leucine rich repeat containing 15 (LRRC15), and phosphodiesterase 3A (PDE3A) expression patterns were similar among related OA cartilage, subchondral bone and synovial tissue arrays in Gene Expression Omnibus database. The Ingenuity Pathway Analysis identified MARCKS to be associated with the outgrowth of neurite, and novel miRNA regulations were proposed to play critical roles in the pathogenesis of the altered OA knee joint microenvironment. The current findings suggest new perspectives in studying novel genes potentially contributing to arthritic joint pain in knee OA, which may assist in finding new targets for OA treatment.

2018-12-18 | GSE110606 | GEO

Identification of synovial fibroblasts subsets associated with pain and progression of knee osteoarthritis

Project description:Background: Synovial inflammation is associated with pain severity in patients with knee osteoarthritis (OA). The aim here was to determine in a population with knee OA, whether synovial tissue from areas associated with pain exhibited different synovial fibroblast transcriptomes, compared to synovial tissue from sites not associated with pain. A further aim was to compare differences between early and end-stage disease synovial fibroblasts. Methods: Patients with early knee OA (n=29) and end-stage knee OA (n=22) were recruited. Patient reported pain was recorded by questionnaire and using an anatomical knee pain map. Proton density fat suppressed MRI axial and sagittal sequences were analysed and scored for synovitis. Synovial tissue was obtained from the medial and lateral parapatellar and suprapatellar sites. RNA sequencing was performed using Illumina’s NextSeq 500 and analysed with Galaxy web platform, usegalaxy.org, and Qlucore software. Transcriptomes were functionally characterised using Ingenuity Pathway Analysis. Findings: Parapatellar synovitis was significantly associated with increased OA pain perception. Functional pathway analysis revealed that early OA painful sites mediate immune cell recruitment and promote the formation and development of neurites. Conclusion: OA disease progression and the presence of pain in early OA is associated with different synovial pathotypes. Further interrogation of these pathotypes will increase our understanding of the role of synovitis in OA joint pain and provide a rationale for the therapeutic targeting to alleviate pain in patients.

2021-10-20 | GSE176223 | GEO

Identification of distinct synovial fibroblast subsets associated with pain and progression of knee osteoarthritis using single-cell RNA sequencing

Project description:Synovial inflammation is associated with pain severity in patients with knee osteoarthritis (OA). The aim here was to determine in a population with knee OA, whether synovial tissue from areas associated with pain exhibited different synovial fibroblast subsets, compared to synovial tissue from sites not associated with pain. A further aim was to compare differences between early and end-stage disease synovial fibroblast subsets. Parapatellar synovitis was significantly associated with the pattern of patient-reported pain in knee OA patients. Synovial tissue from sites of patient-reported pain exhibited a differential transcriptomic phenotype, with distinct synovial fibroblast subsets in early OA and end-stage OA. Functional pathway analysis revealed that synovial tissue and fibroblast subsets from painful sites promoted fibrosis, inflammation and the growth and activity of neurons. The secretome of fibroblasts from early OA painful sites induced neurite outgrowth in dorsal root ganglion neurons. Sites of patient-reported pain in knee OA is associated with a different synovial tissue phenotype and distinct synovial fibroblast subsets. Further interrogation of these fibroblast pathotypes will increase our understanding of the role of synovitis in OA joint pain and provide a rationale for the therapeutic targeting of fibroblast subsets to alleviate pain in patients.

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Therapeutic targets of a new treatment for osteoarthritis composed by curcuminoids extract, hydrolyzed collagen and green tea extract

Project description:We have previously demonstrated that a mixture of curcuminoids extract, hydrolyzed collagen and green tea extract (COT) inhibited inflammatory and catabolic mediatorâ??s synthesis by osteoarthritic (OA) human chondrocytes. The objectives of this study were to identify new targets of COT using genomic approaches. We compared gene expression profiles of chondrocytes treated with COT and/or with interleukin(IL)-1Î². The proteins coded by the most important COT sensitive genes were then quantified by specific immunoassays. Cartilage specimens were obtained from 12 patients (10 women and 2 men; mean age 67 years old, range 54-76 years old) with knee OA. Primary human chondrocytes were cultured in monolayer until confluence and then incubated for 24 hours in the absence or in the presence of human IL-1Î² (10e-11M) and with or without COT, each compound at the concentration of 4 Âµg/ml. Microarray gene expression profiling between control, COT, IL-1Î² and COT IL-1Î² conditions was performed.

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Gene expression pattern of synovial cells from inflammatory and normal areas of osteoarthritis synovial membrane

Project description:The aim of this study was to compare the gene expression pattern of synovial cells from inflammatory (I) or normal/reactive (N/R) areas of a synovial membrane harvested from the same osteoarthritis (OA) patient. This study is the first to identify different expression pattern between two areas of the synovial membrane in the same patient. These differences concern several key pathways involved in OA pathogenesis (inflammation, cartilage metabolism, Wnt signaling and angiogenesis). This analysis also provides interesting information regarding new potent intermediates as potentiel targets for the future therapeutic. Synovial tissues were obtained from 12 knee OA patients at the time of total knee replacement. The inflammatory status of the synovial membrane was characterized according to macroscopic criteria and sorted as N/R and I. Biopsies were cultured separately for 7 days. Microarray gene expression profiling between N/R and I areas was performed.

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Project description:IL-17A has emerged as a pivotal driver of tissue pathology in many immune-mediated inflammatory diseases. Despite sharing 50% sequence homology and the same signalling pathway, the role of IL-17F remains less clear. RNA sequencing of human IL-17 popualtions isolated using a cytokine capture technique identified clear transcriptional differences in IL-17A and IL-17F producing cells, with IL-17A producing cells showing enrichment for cytokine signaling and IL-17F producing cells showing enrichment for cellular replication.

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The expression profiles of extracellular matrix-related genes in the presence or absence of IL-17A or -17F as measured with the PCR array in systemic sclerosis (SSc) dermal fibroblasts

Project description:We examined the effect of IL-17 signaling pathway on extracellular matrix (ECM) expression and the involvement of IL-17 signaling pathway in pathogenesis of SSc. To identify differences in the expression pattern of ECM genes in IL-17A- or IL-17F-treated cells, we performed PCR array analysis, consisting of 84 ECM-related genes. Normal human dermal fibroblasts were cultured until they were confluent, and then stimulated with IL-17A or IL-17F for 12 hours, and total RNA was extracted. A mixture of equal amounts of mRNAs from three normal fibroblasts was prepared in the presence or absence of IL-17A or -17F, and mRNA expression profile was evaluated using PCR Array. Normal fibroblasts were obtained by skin biopsies from 3 healthy donors. Fibroblasts from donors were used and treated separately as indicated in the summary. Equal amount total RNA from each donor was pooled prior to gene expression analysis.

2012-01-01 | E-GEOD-33581 | biostudies-arrayexpress

Osteoarthritis-related changes in gene expression in knee articular chondrocytes in a rat model of osteoarthritis.

Project description:Cartilage destruction in osteoarthritis (OA) results from disturbed chondrocyte metabolism. Here, we used microarrays to show that TGF alpha and CCL2 are simultaneously upregulated in a rat model of OA and cooperate to drive cartilage degradation. The goals of the experiments included here were to a) characterize gene expression in knee joint articular chondrocytes at various stages of development of OA (2 and 8 weeks after surgical induction of OA), and b) to establish trends in gene expression among groups of genes related to the TGF alpha-EGFR axis, over time, in OA. The model chosen to study these results has been previously validated (Appleton, CT et al, 2007, Arthritis Rheum) and used to describe similar gene expression results at a different time point (4 weeks) after induction of OA. The rat model of OA involves surgical destabilization of the knee joint, followed by forced low-intensity mobilization over several weeks; a sham surgery is used as the control (representing a healthy non-OA knee joint) wherein a surgical incision is made but not structural (i.e. ligamentous) modification is made to the joint. Altogether, our data indicate that TGF and CCL2 cooperate to drive cartilage degradation in osteoarthritis. A total of 12 samples were analyzed. 3 replicates were used per condition: OA surgery at 2 weeks, OA surgery at 8 weeks, Sham (control) surgery at 2 weeks and Sham surgery at 8 weeks. Expression of OA samples was assessed relaitve to Sham (control) expression levels.

2012-11-15 | E-GEOD-42295 | biostudies-arrayexpress

The expression profiles of extracellular matrix-related genes in the presence or absence of IL-17A or -17F as measured with the PCR array in systemic sclerosis (SSc) dermal fibroblasts

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