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Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes great distress to patients and society. Early diagnosis is the key to the successful treatment of RA. The basement membrane, one of the oldest tissue structures, is localized under the epithelium. Its complex composition and rich biological functions have made it a focus of research in recent years, while basement membrane-associated genetic variants are involved in most human disease processes. The aim of this study is to find new diagnostic biomarkers for RA and explore their role and possible mechanism in rheumatoid arthritis. The GSE12021, GSE55235 and GSE55457 datasets were downloaded from the GEO database. Their fraction associated with basement membrane genes was analyzed and differentially expressed genes between the disease and normal groups were explored. We identified two basement membrane-associated genes, lysine oxidase-like 1 (LOXL1) and discoid peptide receptor 2 (DDR2). Focusing on the more interesting LOXL1, we found that LOXL1 expression was significantly elevated in the synovium of patients with rheumatoid arthritis, and LOXL1 mRNA and protein levels were elevated in tumor necrosis factor α-stimulated human synovial sarcoma cells (SW982). And LOXL1 knockdown inhibited tumor necrosis factor α-induced inhibition in SW982 cells expression of inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX2), and interleukin-6 (IL-6). Interestingly, knockdown of LOXL1 inhibited the phosphorylation of PI3K and AKT. In summary, LOXL1 may become a novel diagnostic gene for RA, and knockdown of LoxL1 may inhibit synovial inflammation by affecting PI3K/AKT pathway.

SUBMITTER: Hu J

PROVIDER: S-EPMC10817408 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development.

Hu Jiawei J Liu Xuqiang X Xu Qiang Q Zhu Meisong M Wang Song S Quan Kun K Dai Min M Mo Fengbo F Zhan Haibo H

Aging 20240112 1

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes great distress to patients and society. Early diagnosis is the key to the successful treatment of RA. The basement membrane, one of the oldest tissue structures, is localized under the epithelium. Its complex composition and rich biological functions have made it a focus of research in recent years, while basement membrane-associated genetic variants are involved in most human disease processes. The aim of this study i ...[more]

PMID: 38217541

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Project description:In recent years microarray technology has been used increasingly to acquire knowledge about the pathogenic processes involved in rheumatoid arthritis. The present study investigated variations in gene expression in synovial tissues within and between patients with rheumatoid arthritis. This was done by applying microarray technology on multiple synovial biopsies obtained from the same knee joints. In this way the relative levels of intra-patient and inter-patient variation could be assessed. The biopsies were obtained from 13 different patients: 7 by orthopedic surgery and 6 by rheumatic arthroscopy. The data show that levels of heterogeneity varied substantially between the biopsies, because the number of genes found to be differentially expressed between pairs of biopsies from the same knee ranged from 6 to 2,133. Both arthroscopic and orthopedic biopsies were examined, allowing us to compare the two sampling methods. We found that the average number of differentially expressed genes between biopsies from the same patient was about three times larger in orthopedic than in arthroscopic biopsies. Using a parallel analysis of the tissues by immunohistochemistry, we also identified orthopedic biopsies that were unsuitable for gene expression analysis of synovial inflammation due to sampling of non-inflamed parts of the tissue. Removing these biopsies reduced the average number of differentially expressed genes between the orthopedic biopsies from 455 to 171, in comparison with 143 for the arthroscopic biopsies. Hierarchical clustering analysis showed that the remaining orthopedic and arthroscopic biopsies had gene expression signatures that were unique for each patient, apparently reflecting patient variation rather than tissue heterogeneity. Subsets of genes found to vary between biopsies were investigated for overrepresentation of biological processes by using gene ontology. This revealed representative 'themes' likely to vary between synovial biopsies affected by inflammatory disease.

Project description:BACKGROUND:We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). The exact mechanism of AD in promoting joint destruction remains unclear. Osteopontin (OPN) is required for osteoclast recruitment. We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. This study aimed to evaluate a novel role for AD in RA. METHODS:The serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA). AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue. Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively. Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co-culture system. Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing. The expression levels of OPN and integrin αvβ3 in the ankle joint tissues of the mice were examined by double immunofluorescence. RESULTS:Our results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum. The AD distribution was coincident with that of OPN in the RA synovial tissue. AD stimulation of RASFs increased OPN production in a dose-dependent manner. AD-treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN. Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice. When bound to integrin αvβ3, OPN functions as a mediator of AD and osteoclasts. CONCLUSIONS:Our study provides new evidence of AD involvement in bone erosion. AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion. These data highlight AD as a novel target for RA treatment.

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Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development.

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Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development.

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