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Rheumatoid arthritis: the old issue, the new therapeutic approach.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease of unknown etiology. The most common form of this disease is chronic inflammatory arthritis, which begins with inflammation of the synovial membrane of the affected joints and eventually leads to disability of the affected limb. Despite significant advances in RA pharmaceutical therapies and the availability of a variety of medicines on the market, none of the available medicinal therapies has been able to completely cure the disease. In addition, a significant percentage (30-40%) of patients do not respond appropriately to any of the available medicines. Recently, mesenchymal stromal cells (MSCs) have shown promising results in controlling inflammatory and autoimmune diseases, including RA. Experimental studies and clinical trials have demonstrated the high power of MSCs in modulating the immune system. In this article, we first examine the mechanism of RA disease, the role of cytokines and existing medicinal therapies. We then discuss the immunomodulatory function of MSCs from different perspectives. Our understanding of how MSCs work in suppressing the immune system will lead to better utilization of these cells as a promising tool in the treatment of autoimmune diseases.

SUBMITTER: Babaahmadi M

PROVIDER: S-EPMC10518102 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Rheumatoid arthritis: the old issue, the new therapeutic approach.

Babaahmadi Mahnaz M Tayebi Behnoosh B Gholipour Nima Makvand NM Kamardi Mehrnaz Tayebi MT Heidari Sahel S Baharvand Hossein H Eslaminejad Mohamadreza Baghaban MB Hajizadeh-Saffar Ensiyeh E Hassani Seyedeh-Nafiseh SN

Stem cell research & therapy 20230923 1

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease of unknown etiology. The most common form of this disease is chronic inflammatory arthritis, which begins with inflammation of the synovial membrane of the affected joints and eventually leads to disability of the affected limb. Despite significant advances in RA pharmaceutical therapies and the availability of a variety of medicines on the market, none of the available medicinal therapies has been able to completely cure the ...[more]

PMID: 37741991

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Project description:ObjectiveRheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint damage, including cartilage degradation and bone erosion. Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, plays a key role in osteogenesis and tissue repair. However, its role in bone erosion and inflammation in RA remains underexplored. This study aims to evaluate BMP9's therapeutic potential in RA, focusing on its effects on bone destruction, osteogenesis, and inflammation.Materials and methodsIn this study, BMP9 expression was analyzed in synovial tissues from RA and osteoarthritis patients and in the ankle joints of collagen-induced arthritis (CIA) mice using immunohistochemistry, qRT-PCR, and Western blotting. The therapeutic effect of BMP9 on bone destruction was evaluated in a CIA mouse model through micro-CT imaging, histological analysis, and clinical scoring. Osteogenic differentiation was assessed by alkaline phosphatase and Alizarin Red S staining, while osteoclast activity was examined through tartrate-resistant acid phosphatase staining. Fluorescence double-labeling was used to track new bone formation. Data were analyzed using (Statistical Package for the Social Sciences) SPSS, and appropriate statistical tests were performed to determine significance.ResultsIn this study, BMP9 expression was significantly down-regulated in the synovial tissue of RA patients and in the ankle joints of CIA mice. BMP9 treatment in CIA mice ameliorated joint inflammation, as shown by reduced limb swelling, lower arthritis index, and improved tissue morphology. Furthermore, BMP9 significantly alleviated bone loss, as evidenced by increased bone mineral density and trabecular structure. However, BMP9 treatment did not significantly impact osteoclastogenesis or bone resorption. BMP9 also enhanced bone mineralization and formation, as shown by increased mineral apposition rate and bone formation rate. Additionally, BMP9 promoted osteogenic differentiation of synovial cells, enhancing alkaline phosphatase activity and mineral nodule formation. These results suggest that BMP9 has a protective effect on joint inflammation and bone loss in RA, potentially through promoting bone formation without influencing osteoclast activity.ConclusionOur study concludes that targeting BMP9 alleviates inflammation and promotes osteogenic differentiation in RA, highlighting BMP9 as a promising therapeutic target for addressing bone destruction in RA.

Project description:ObjectivesAlterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question.MethodsTargeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model.ResultsDifferential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model.ConclusionsAltogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.

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Rheumatoid arthritis: the old issue, the new therapeutic approach.

Publications

Rheumatoid arthritis: the old issue, the new therapeutic approach.

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