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

Bhagavatham, SKS and Khanchandani, P and Kannan, V and Potikuri, D and Sridharan, D and Pulukool, SK and Naik, AA and Dandamudi, RB and Divi, SM and Pargaonkar, A and Ray, R and Santha, SSR and Seshagiri, PB and Narasimhan, K and Gumdal, N and Sivaramakrishnan, V (2021) Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis. In: Scientific Reports, 11 (1).

	PDF sci_rep_11-01_2021 - Published Version Download (5MB)
Preview	PDF 41598_2021_94607_MOESM1_ESM.pdf - Published Supplemental Material Download (1MB) | Preview

Abstract

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. © 2021, The Author(s).

Item Type:	Journal Article
Publication:	Scientific Reports
Publisher:	Nature Research
Additional Information:	The copyright for this article belongs to Authors
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	24 Sep 2021 07:55
Last Modified:	24 Sep 2021 07:55
URI:	http://eprints.iisc.ac.in/id/eprint/69730

Actions (login required)

View Item