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

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.

SUBMITTER: Bhagavatham SKS

PROVIDER: S-EPMC8302689 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Bhagavatham Sai Krishna Srimadh SKS Khanchandani Prakash P Kannan Vishnu V Potikuri Damodaram D Sridharan Divya D Pulukool Sujith Kumar SK Naik Ashwin Ashok AA Dandamudi Rajesh Babu RB Divi Sai Mangala SM Pargaonkar Ashish A Ray Rahul R Santha Saibharath Simha Reddy SSR Seshagiri Polani B PB Narasimhan K K Gumdal Narsimulu N Sivaramakrishnan Venketesh V

Scientific reports 20210723 1

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 ...[more]

PMID: 34301999

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Project description:ObjectiveRheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non-fingers, with the aim of analyzing which factors are associated with destruction of the finger joints.MethodsA total of 1,215 Japanese patients with RA were recruited from 2 different populations. The degree of joint destruction was assessed using the total modified Sharp/van der Heijde score (SHS) of radiographic joint damage. The SHS score of joint damage in the finger joints was used as the dependent variable, and the SHS score in the non-finger joints was used as a covariate. Age, sex, disease duration, smoking, C-reactive protein level, treatment for RA, and positivity for and levels of anti-citrullinated protein antibodies and rheumatoid factor (RF) were evaluated as candidate correlates. Overall effect sizes were assessed in a meta-analysis. In addition, associations observed in the Japanese patients were compared to those in a cohort of 157 Dutch RA patients in the BeSt study (a randomized, controlled trial involving 4 different strictly specified treatment strategies for early RA).ResultsNot surprisingly, disease duration in Japanese patients with RA was associated with the finger SHS score (P ≤ 0.00037). Both positivity for and levels of RF showed significant associations with the finger SHS score after adjustment for covariates (P = 0.0022 and P = 8.1 × 10(-7) , respectively). These associations were also true in relation to the time-averaged finger SHS score. An association between RF positivity and the finger SHS score was also observed in Dutch patients with RA in the BeSt study (P = 0.049).ConclusionPositivity for and levels of RF are associated with finger joint destruction independent of non-finger joint destruction and other covariates. Our findings suggest that there are different mechanisms of joint destruction operating in the finger joints of patients with RA.

Project description:IntroductionProgression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.Methods1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.ResultsWe found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10-4). This variant was also significant after Bonferroni correction.ConclusionsThese results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.

Project description:BackgroundThe study compares the clinical outcomes of first metatarsophalangeal (MTP) joint fusion vs joint-preserving surgery in rheumatoid arthritis (RA) patients with severe forefoot deformities.MethodsThis single-center retrospective study at Kyushu University Hospital reviewed RA patients who underwent either first MTP joint arthrodesis or joint-preserving surgery for hallux valgus (HV) deformity between January 2008 and December 2022. A total of 103 feet (73 cases) were analyzed, with 75 feet (58 cases) showing radiographic bone destruction of Larsen grade 3 or higher. One foot underwent resection arthroplasty, so ultimately 74 feet in 57 cases were evaluated. Surgical procedures included joint-preserving biplane osteotomy or arthrodesis with crossed screws. Clinical outcomes were measured using the Japanese Society for Surgery of the Foot (JSSF) Hallux scale, whereas radiographic assessments included HV angle (HVA). Propensity score matching was used to minimize bias when comparing postoperative outcomes between the arthrodesis and joint-preserving surgery groups.ResultsThis study analyzed 74 feet undergoing either arthrodesis (27 feet) or joint-preserving surgery (47 feet) for HV. Patients in the 2 groups showed similar demographic and clinical characteristics except with respect to length of follow-up, which was greater in the arthrodesis group (5.1 ± 2.6 years vs 2.4 ± 2.0 years, P < .01) than the joint-preserving group. In the arthrodesis group, all patients underwent resection arthroplasty on the second to fifth toes. The joint-preserving group included first MTP joint surgery alone (n = 5) and first MTP joint and lesser MTP joint surgeries (resection arthroplasty, n = 29; joint-preserving surgery, n = 13). Functional scores significantly improved in both groups, with first metatarsophalangeal joint-preserving surgery yielding better postoperative outcomes. In cases of deformity recurrence, the recurrent cases exhibited greater immediate postsurgical HVA, but other foot function outcomes remained similar at the end of follow-up.ConclusionJoint-preserving surgery for advanced rheumatoid forefoot deformity showed better functional improvement than arthrodesis using the propensity score matching and comparable clinical outcomes, highlighting it as a potential treatment option for severe joint destruction.Level of evidenceLevel Ⅳ, retrospective study.

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

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

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