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Merck

Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis.

Scientific reports (2021-07-25)
Sai Krishna Srimadh Bhagavatham, Prakash Khanchandani, Vishnu Kannan, Damodaram Potikuri, Divya Sridharan, Sujith Kumar Pulukool, Ashwin Ashok Naik, Rajesh Babu Dandamudi, Sai Mangala Divi, Ashish Pargaonkar, Rahul Ray, Saibharath Simha Reddy Santha, Polani B Seshagiri, K Narasimhan, Narsimulu Gumdal, Venketesh Sivaramakrishnan
RESUMEN

Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades adenosine, an anti-inflammatory molecule, resulting in an inflammatory bias. We present an integrative analysis of clinical data, cytokines, serum metabolomics in RA patients and mechanistic studies on ADA-mediated effects on in vitro cell culture models. ADA activity differentiated patients into low and high ADA sets. The levels of the cytokines TNFα, IFNγ, IL-10, TGFβ and sRANKL were elevated in RA and more pronounced in high ADA sets. Serum metabolomic analysis shows altered metabolic pathways in RA which were distinct between low and high ADA sets. Comparative analysis with previous studies shows similar pathways are modulated by DMARDs and biologics. Random forest analysis distinguished RA from control by methyl-histidine and hydroxyisocaproic acid, while hexose-phosphate and fructose-6-phosphate distinguished high ADA from low ADA. The deregulated metabolic pathways of High ADA datasets significantly overlapped with high ADA expressing PBMCs GEO transcriptomics dataset. ADA induced the death of chondrocytes, synoviocyte proliferation, both inflammation in macrophages and their differentiation into osteoclasts and impaired differentiation of mesenchymal stem cells to osteoblasts and mineralization. PBMCs expressing elevated ADA had increased expression of cytokines and P2 receptors compared to synovial macrophages which has low expression of ADA. Our data demonstrates increased cytokine levels and distinct metabolic signatures of RA based on the ADA activity, suggests an important role for ADA in the pathophysiology of RA joints and as a potential marker and therapeutic target in RA patients.

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Ácido L-ascórbico, suitable for cell culture, suitable for plant cell culture, ≥98%
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DCFHDA, BioReagent, suitable for fluorescence, ≥95% (HPLC)
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β-Glycerol phosphate disodium salt pentahydrate, ≥98.0% (NT)
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Alizarin Red S, certified by the Biological Stain Commission
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Fast Red TR Salt 1,5-naphthalenedisulfonate salt