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The long-non coding RNA HOTAIR shapes the inflammatory response in joints of the lower extremity

ABSTRACT: Various forms of chronic arthritis like osteoarthritis (OA) or rheumatoid arthritis (RA) are major causes of disability and represent a global burden on health care systems. Inter- and intraindividual differences in the phenotype of arthritis often prevent early diagnosis and effective treatment. Previously, we suggested that site-specific differences in the joint stroma influence the development and the outcome of arthritis and showed that the long non-coding RNA HOTAIR is expressed exclusively in synovial fibroblasts (SF) of lower joints. Here, we further analysed the function of HOTAIR in SF and in arthritis development. We show that joint-specific HOTAIR expression in SF is stronlgy imprinted in the chromatin landscape of SF by epigenetic mechanisms. Nevertheless, HOTAIR expression in knee SF was downregulated by inflammatory cytokines. Accordingly, HOTAIR was more expressed in OA tissues than in RA tissues. Downregulation of HOTAIR regulated relevant arthritis pathways by epigenetic and transcriptional mechanisms and modified the migratory function of SF, decreased SF mediated osteoclastogenesis, and increased the attraction of B cells by SF. We propose that HOTAIR downregulation in inflammation epigenetically regulates important pathways and functions in SF, and thus modulates the phenotype of arthritis in lower extremity joints.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185440 | GEO | 2023/01/01

REPOSITORIES: GEO

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Project description:Osteoarthritis (OA) of the hand is a common disease resulting in pain and impaired function. The pathogenesis of hand OA (HOA) is elusive and models to study it have not been described so far. Culture of chondrocytes is a model to study the development of cartilage degeneration, which is a hallmark of OA and well established in OA of the knee and hip. In the current study we investigated the feasibility human chondrocyte culture derived from proximal interphalangeal (PIP) finger joints of dissecting room cadavers. Index and middle fingers without signs of osteoarthritis were obtained from 30 cadavers using two different protocols. Hyaline cartilage from both articulating surfaces of the proximal interphalangeal (PIP) joint was harvested and digested in collagenase. Cultured chondrocytes were monitored for contamination, viability, and expression of chondrocyte specific genes. Chondrocytes derived from knee joints of the cadavers were cultured under identical conditions. Gene expression comparing chondrocytes from PIP and knee joints was carried out using Affymetrix GeneChip Human 2.0 ST arrays. The resulting differentially expressed genes were validated by real-time PCR and immunohistochemistry.Chondrocytes harvested up to 101 hours after death of the donors were viable. mRNA expression of collagen 2A1, aggrecan and Sox9 was significantly higher in chondrocytes as compared to cultured fibroblasts. Comparison of gene expression by chondrocytes from PIP and knee joints yielded 528 differentially expressed genes. Chondrocytes from the same joint region had a higher grade of similarity than chondrocytes of the same individual. These results were validated using real-time PCR and immunohistochemistry.We demonstrate for the first time a reliable method for culture of chondrocytes derived from PIP joints. PIP chondrocytes show a specific gene expression pattern and could be used as tool to study cartilage degeneration in HOA. Three samples of cultured chondrocytes from knee and proximal interphalangeal finger joints were compared. Gene expression of the four most differentially regulated genes was confirmed by real-time PCR in 10 independent samples.

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The long-non coding RNA HOTAIR shapes the inflammatory response in joints of the lower extremity

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