ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies.
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ABSTRACT:
SUBMITTER: Jiang L
PROVIDER: S-EPMC8381022 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aggrecanase-2 (ADAMTS5) gene is responsible for aggrecan degradation that may contribute to cartilage destruction in a mouse osteoarthritis (OA) model. We aimed to investigate the effects of ADAMTS5 gene polymorphisms on OA risk in a Chinese population. A total of 300 OA patients and 300 controls were recruited and their genotypes for ADAMTS5 gene rs226794 and rs2830585 polymorphisms were determined using a custom-by-design 48-Plex single nucleotide polymorphism Scan™ kit. ADAMTS5-associated genes were identified by co-expression analysis and their functions were investigated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Bioinformatics analysis showed that ADAMTS5 was significantly related to the components, structural constituent, and organization of the extracellular matrix. The rs2830585 polymorphism, but not rs226794 polymorphism, was significantly associated with an increased risk of knee OA. Stratified analysis further confirmed this significant association in patients at age ≥55 years. In conclusion, the ADAMTS5 rs2830585 polymorphism may be involved in the development of knee OA by destroying the extracellular matrix, but this finding should be further confirmed by larger studies.
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Project description:PurposeIn order to further study the biological functions of glutathione peroxidases (GPXs) and their expression level in patients with osteoarthritis (OA), we fully explored the potential relationship between GPXs and OA. This will provide new ideas for basic biological studies and therapeutic strategies for OA patients.Patients and methodsIn this study, bioinformatics techniques were used to explore the biological functions of five GPXs. The core genes related to the biological functions of GPXs were identified by constructing a protein-protein interaction network (PPI). In addition, we utilized microarray data in public databases to analyze the expression levels of GPXs in OA patients and healthy controls. Finally, we used quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of GPXs in OA patients and controls to validate our bioinformatic analysis results.ResultsEnrichment analysis showed GPXs were mainly enriched in the glutathione metabolic pathway and participate in the biological process of oxidative stress response, and further play an antioxidant role. The PPI network indicated that superoxide dismutase 1 (SOD1), superoxide dismutase 2(SOD2) and catalase (CAT) were the core proteins of this network. GPX1 was regulated by the greatest number of miRNAs. Experiments showed that the expression of GPX1 was elevated in OA patients compared with controls.ConclusionGPXs play an important antioxidant role in oxidative stress response. The expression of GPX1 was elevated in peripheral blood mononuclear cells (PBMCs) of OA patients. The changes of GPXs in OA patients may regulate the level of oxidative stress, which may influence synovial lesions and chondrocyte apoptosis.
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Project description:Arthritis, defined as a chronic inflammation often accompanied by swelling of one or more joints, encompasses more than 100 conditions that affect the joints, tissues around them as well as other connective tissues. This condition causes severe discomfort compromising the quality of life drastically, and thereby inflicts severe financial and social impact on the people affected. The incidence rate of arthritis is increasing all around the globe including the United States every year. In general, osteoarthritis (OA) affects more people in comparison to rheumatoid arthritis (RA). In the USA itself, more than 14 million people are affected by OA in comparison to 1.4 million people suffering from RA. In both conditions, elevated levels of proinflammatory cytokines have been recorded, this incidence generally precedes the cartilage degradation observed in the patients. The use of mesenchymal stem cells (MSCs) has proven to be a safe and efficient therapeutic option for treating many inflammation-rooted pathological conditions. Evidence suggests that MSCs down-regulate the effects of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1B, IL-2, and IL-17, and help restore the functions of immune cells. In addition, these cells promote the polarization of M2 phenotype macrophages, thus contributing to the suppression of the inflammatory process and consequentially to cartilage regeneration. Preclinical and clinical trials have proven the safety and effectiveness of this therapy, supported by the fact that these do not provoke any host immune response, and their influence on the cytokine profiles. An attempt to survey the results of stem cell therapy for treating arthritis has been carried out in this review.
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