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| Open AccessBoth microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis
Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
- Yoshiaki Ito
- , Tokio Matsuzaki
- & Hiroshi Asahara
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Article
| Open AccessLasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis
Fibroblast-like synoviocytes are important mediators of joint pathology in rheumatoid arthritis (RA). Here the authors show that Lasp1 is epigenetically regulated and highly expressed by these cells in RA and its deletion can limit joint pathology in a mouse model of inflammatory arthritis.
- Denise Beckmann
- , Anja Römer-Hillmann
- & Adelheid Korb-Pap
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Article
| Open AccessPhase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.
- Sarfaraz A. Hasni
- , Sarthak Gupta
- & Mariana J. Kaplan
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| Open AccessConserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation
T regulatory (Treg) cells can differentiate into effector Treg (eTreg) cells that might be functional in inflammatory diseases. Using RNA sequencing and epigenetic profiling, the authors show that eTreg signatures in juvenile idiopathic arthritis joints are similar to tumour microenvironment (TME) Treg cells and are affected by tissue-specific epigenetic regulation.
- Gerdien Mijnheer
- , Lisanne Lutter
- & Femke van Wijk
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Article
| Open AccessLoss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis
Dysregulation of synovial fibroblasts is thought to be an important step in the pathogenesis of rheumatoid arthritis. Here the authors implicate α2-6 sialylation in this process by studying the glycome of these cells in patients and in a mouse model of inflammatory joint disease.
- Yilin Wang
- , Aneesah Khan
- & Miguel A. Pineda
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Article
| Open AccessTargeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis
Celastrol might be useful in treating rheumatoid arthritis in part by inhibiting apoptosis of macrophages; however, systemic toxicity is a concern. Here the authors design celastrol-loaded nanoparticles that release a payload in response to MMP9 cleavage and show these NPs are effective at inducing apoptosis of human macrophages in vitro and a therapeutic effect with an adjuvant-induced arthritis model in rats.
- Caifeng Deng
- , Quan Zhang
- & Zhirong Zhang
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Article
| Open AccessType I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
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Article
| Open AccessMechanical stress determines the configuration of TGFβ activation in articular cartilage
The functional relationship between subchondral bone and articular cartilage is unclear. Here, the authors show that transforming growth factor-beta propagates the mechanical impact of subchondral bone on articular cartilage through αV integrin–talin mechanical transduction system in chondrocytes.
- Gehua Zhen
- , Qiaoyue Guo
- & Xu Cao
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Article
| Open AccessGlobal discovery of lupus genetic risk variant allelic enhancer activity
Thousands of genetic variants have been associated with lupus, but causal variants and mechanisms are unknown. Here, the authors combine a massively parallel reporter assay with genome-wide ChIP experiments to identify risk variants with allelic enhancer activity mediated through transcription factor binding.
- Xiaoming Lu
- , Xiaoting Chen
- & Leah C. Kottyan
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Article
| Open AccessArachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation
ORAI3 is part of pore forming calcium channels involved in T cell activation. Here the authors show that there is increased expression of ORAI3 in T cells from patients with rheumatoid arthritis and that the transcription factor IKAROS negatively regulates the ORAI3 promoter, indicating a regulatory loop that can control auto-reactivity of T cells in these patients.
- Zhongde Ye
- , Yi Shen
- & Jörg J. Goronzy
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Article
| Open AccessIdentification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups
The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.
- Yong-Fei Wang
- , Yan Zhang
- & Wanling Yang
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Article
| Open AccessOsteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins
The innate immune system and inflammation modulate bone homeostasis through complex regulation of bone remodelling cells including osteoblasts and osteoclasts. Here, the authors show that the type I interferon pathway and guanylate binding proteins functionally limit bone loss by inhibiting osteoclast functions.
- David E. Place
- , R. K. Subbarao Malireddi
- & Thirumala-Devi Kanneganti
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Article
| Open AccessSingle cell transcriptomic analysis of human pluripotent stem cell chondrogenesis
Application of human induced pluripotent stem cells (hiPSCs) for tissue regeneration is hindered by off-target cell differentiation. Here, the authors use bulk and single cell RNA-sequencing to identify WNT and MITF as off-target hubs during chondrogenic differentiation; inhibiting these pathways enhanced homogeneity and yield.
- Chia-Lung Wu
- , Amanda Dicks
- & Farshid Guilak
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Article
| Open AccessTARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens
TARM1 is a LILR family member that drives cell signalling via interactions with FcRγ. Here the authors show that TARM1 binds collagens to activate dendritic cells and thereby is an effector of inflammatory arthritis, plus provide a soluble TARM-Fc fusion protein that can limit collagen-induced arthritis in mice.
- Rikio Yabe
- , Soo-Hyun Chung
- & Yoichiro Iwakura
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Article
| Open AccessFunctionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity
Type I interferon drives autoimmune pathology in SLE and has been assumed to come predominantly from plasmacytoid dendritic cells (pDCs). Here, the authors show that prior to the onset of SLE, pDCs lose multiple immunogenic functions and, instead, non-hematopoietic cells such as keratinocytes are a major source of type I interferons.
- Antonios Psarras
- , Adewonuola Alase
- & Edward M. Vital
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Article
| Open AccessBlood pro-resolving mediators are linked with synovial pathology and are predictive of DMARD responsiveness in rheumatoid arthritis
Being able to predict the therapeutic benefit of disease modifying anti-rheumatic drugs (DMARDs) would be of great benefit and a stepping stone towards personalized medicine. Here the authors use machine learning and lipid mediator mass spectrometry to show specialized pro-resolving mediators are indicative of DMARD responsiveness among rheumatoid arthritis patients.
- Esteban A. Gomez
- , Romain A. Colas
- & Jesmond Dalli
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Article
| Open AccessOsteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation
Osteoarthritis (OA) is associated with cartilage disruption, but the underlying mechanisms remain unclear. Here, the authors show that expression of osteoclast-associated receptor (OSCAR) is associated with OA, that its genetic ablation or targeting with OSCAR-Fc fusion protein ameliorates OA in mice by decreasing chondrocyte apoptosis.
- Doo Ri Park
- , Jihee Kim
- & Soo Young Lee
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Article
| Open AccessPatients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion
Cytokine storm seems to be a common feature of severe COVID-19 pathology. Here, the authors show a reduced rate of SARS-CoV2 positivity in a large population of patients with immune-mediated inflammatory diseases if they are already being treated with cytokine or JAK inhibitors, indicating these treatments are safe to continue and are possibly protective against COVID19.
- David Simon
- , Koray Tascilar
- & Georg Schett
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Article
| Open AccessLDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis
Chondrocytes have altered cellular metabolism in the context of osteoarthritis, but whether and how these changes are associated with inflammation is a controversial area. Here the authors show that inflammatory NF-κB signalling drives a glycolytic shift in chondrocytes and the production of ROS, which drives cartilage catabolism.
- Manoj Arra
- , Gaurav Swarnkar
- & Yousef Abu-Amer
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Article
| Open AccessPiezo2 expressed in proprioceptive neurons is essential for skeletal integrity
Mutations in human PIEZO2, encoding for a mechanosensitive ion channel, lead to skeletal abnormalities including scoliosis and hip dysplasia. Here, the authors show that deletion of Piezo2 in proprioceptive neurons, but not in skeletal lineages, recapitulated the human phenotype in mice.
- Eran Assaraf
- , Ronen Blecher
- & Elazar Zelzer
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Article
| Open AccessSystemic lupus erythematosus favors the generation of IL-17 producing double negative T cells
Splenic marginal zone macrophages can establish immune tolerance and limit the development of systemic lupus erythematosus (SLE). Here the authors show that these cells do this by clearing apoptotic cells, and defects in these cells result in the generation of self-reactive double negative T cells that are known to contribute to SLE pathogenesis.
- Hao Li
- , Iannis E. Adamopoulos
- & George C. Tsokos
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Article
| Open AccessThe ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion
The common ABCG2 variant Q141K contributes to hyperuricemia and gout risk. Here, using a human interventional study and a new orthologous mouse model, the authors report a tissue specific pathobiology of the Q141K variant, and support a significant role for ABCG2 in urate excretion in both the kidney and intestine.
- Kazi Mirajul Hoque
- , Eryn E. Dixon
- & Owen M. Woodward
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Article
| Open AccessTargeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis
Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases. Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.
- Narges Tajik
- , Michael Frech
- & Mario M. Zaiss
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Article
| Open AccessEthanol consumption inhibits TFH cell responses and the development of autoimmune arthritis
Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells.
- Vugar Azizov
- , Katharina Dietel
- & Mario M. Zaiss
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Article
| Open AccessScavenger receptor-A is a biomarker and effector of rheumatoid arthritis: A large-scale multicenter study
Scavenger receptor-A (SR-A) is mostly expressed by myeloid cells and has been attributed a variety of biological functions. Here the authors assess SR-A as a biomarker for diagnosis of rheumatoid arthritis (RA) using large-scale training and validation cohorts and show that modulating SR-A levels can alter progression of collagen-induced arthritis in mice.
- Fanlei Hu
- , Xiang Jiang
- & Zhanguo Li
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Article
| Open AccessLupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory
Systemic lupus erythematosus (SLE) is an autoimmune disorder which can have neurological manifestations, including autoantibody targeting of the NMDA receptor. In this study, the authors GluN2A subunit is a target of SLE autoantibodies, using sample derived from patient.
- Kelvin Chan
- , Jacquelyn Nestor
- & Lonnie P. Wollmuth
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Article
| Open AccessExercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors
Some exercises exacerbate chronic inflammation and muscle fibrosis in chronic myopathy. Here, the authors show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise induces muscle regeneration, and impaired FAP senescence worsens inflammation and fibrosis in chronic myopathy in mice.
- Yuki Saito
- , Takako S. Chikenji
- & Mineko Fujimiya
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Article
| Open AccessTherapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
Fibroblast hyper-activation and proliferation is a major feature in arthritis, yet scarcely addressed for anti-arthritic therapies. Here, the authors show that activation of the MC1 receptor induces fibroblast senescence associated with a reparative phenotype, ultimately regulating experimental inflammatory arthritis.
- Trinidad Montero-Melendez
- , Ai Nagano
- & Mauro Perretti
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Article
| Open AccessEnvironmental arginine controls multinuclear giant cell metabolism and formation
Multinucleated giant cells (MGCs) are important in the pathogenesis of various diseases. Here, the authors demonstrate that extracellular presence of the amino acid arginine is required for MGC formation and metabolism, suggesting a translational impact for strategies utilizing systemic arginine depletion in MGC-mediated diseases.
- Julia S. Brunner
- , Loan Vulliard
- & Gernot Schabbauer
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Article
| Open AccessGM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis
Spondyloarthritis pathology is manifested by increased myeloid infiltration of the joints. Here the authors show that in a mouse model of spondyloarthritis, a single dose of a microbial ligand curdlan induces persistent extramedullary myelopoiesis in the spleen and joints, which is driven by GM-CSF and can be amplified by exogenous IL-33.
- Daniel Regan-Komito
- , James W. Swann
- & Thibault Griseri
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Article
| Open AccessHeritability of skewed X-inactivation in female twins is tissue-specific and associated with age
Skewing of X chromosome inactivation (XCI) occurs when the silencing of one parental X chromosome is non-random. Here, Zito et al. report XCI patterns in lymphoblastoid cell lines, blood, subcutaneous adipose tissue samples and skin samples of monozygotic and dizygotic twins and find XCI skew to associate with tissue and age.
- Antonino Zito
- , Matthew N. Davies
- & Kerrin S. Small
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Article
| Open AccessGenome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).
- Paul A Lyons
- , James E Peters
- & Kenneth G. C. Smith
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Article
| Open AccessGWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that affects the connective tissue. Here, López-Isac et al. identify 13 new risk loci for SSc as well as loci specific for limited cutaneous and diffuse SSc and, defining credible sets and performing functional annotation, highlight key pathways and cell types for SSc.
- Elena López-Isac
- , Marialbert Acosta-Herrera
- & Javier Martin
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Article
| Open AccessTankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation
Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.
- Sukyeong Kim
- , Sangbin Han
- & Jin-Hong Kim
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Article
| Open AccessIntestinal microbiome composition and its relation to joint pain and inflammation
Alterations to the microbiome are now associated with various diseases. Here the authors analyze microbiomes from a large population based cohort and show positive correlations between abundance of Streptococcus spp. and osteoarthritis-related knee pain.
- Cindy G. Boer
- , Djawad Radjabzadeh
- & Joyce B. J. van Meurs
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Article
| Open AccessContext-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele
Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of monocytes in IL-7-related autoimmunity.
- Hussein Al-Mossawi
- , Nicole Yager
- & Benjamin P. Fairfax
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Article
| Open AccessHIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis
Leflunomide is used for the treatment of rheumatoid arthritis. Here, the authors show that effectiveness is limited in patients with higher levels of serum c-reactive protein (CRP). Using animal models, they show that higher CRP induces HIF1a expression, which in turn interferes with Leflunomide signalling, and that effectiveness of the drug is restored when HIF1a is pharmacologically inhibited.
- Chao Liang
- , Jie Li
- & Aiping Lu
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Article
| Open AccessA phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease of substantial phenotypic heterogeneity in different ethnic groups. Here, using data from a multi-ethnic cohort, the authors describe an approach based on clinical and molecular data to subtype SLE patients into three clusters of severity.
- Cristina M. Lanata
- , Ishan Paranjpe
- & Lindsey A. Criswell
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Article
| Open AccessA plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity
Autoreactivity to myeloperoxidase (MPO) causes autoimmune vasculitis and severe glomerulonephritis. Here, Ooi et al. show that a Staphylococcus aureus plasmid encodes a peptide that is homologous to an immunodominant MPO epitope and induces anti-MPO autoimmunity and glomerulonephritis in mice.
- Joshua D. Ooi
- , Jhih-Hang Jiang
- & A. Richard Kitching
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Article
| Open AccessBone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis
The adaptor protein SHN3 suppresses new bone formation by controlling osteoblast activity. Here, the authors show that ablation of SHN3 function, either genetically or by delivering an artificial miRNA via AAV9, rescues bone loss in osteoporotic mice, and show that engineering of the AAV9 capsid improves targeting to bone
- Yeon-Suk Yang
- , Jun Xie
- & Jae-Hyuck Shim
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Article
| Open AccessThe microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression
Osteoarthritis involves whole-joint tissue degeneration. Here, the authors show that miR-204 and miR-211 in mesenchymal joint cells regulate their proliferation, catabolic and osteogenic responses, and that disease progression is ameliorated by intra-articular miR-204 delivery in mice.
- Jian Huang
- , Lan Zhao
- & Di Chen
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Article
| Open AccessTGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
Increased inflammation during ageing promotes osteoporosis by activating osteoclast function and inhibiting osteoblasts. Here, the authors show that TGFβ1 release from bone matrix during ageing induces degradation of TRAF3 in mesenchymal progenitor cells, leading to reduced osteoblast differentiation and increased osteoclast formation, and suggesting that pharmacological stabilization of TRAF3 could ameliorate age-related osteoporosis.
- Jinbo Li
- , Akram Ayoub
- & Brendan F. Boyce
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Article
| Open AccessMesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients
Promising pilot clinical trials of mesenchymal stem cells (MSCs) therapy of lupus await validation in larger, controlled trials. Here the authors show that MSCs expand CD1c+ dendritic cells in cell culture by producing FLT3L, and that in lupus patients, circulating CD1c+ dendritic cells and FLT3L are increased following MSCs therapy.
- Xinran Yuan
- , Xiaodong Qin
- & Lingyun Sun
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Article
| Open AccessFunctional testing of thousands of osteoarthritis-associated variants for regulatory activity
GWAS have identified risk loci for osteoarthritis (OA), but the causal variants still have to be determined. Here, the authors apply a massively-parallel reporter assay to screen 1,605 candidate SNPs in 35 OA loci, which prioritizes six SNPs in four loci, one of which, rs4730222, is characterized in more detail.
- Jason C. Klein
- , Aidan Keith
- & Jay Shendure
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Article
| Open AccessWwp2 maintains cartilage homeostasis through regulation of Adamts5
Wwp2 is an HECT-type E3 ubiquitin ligase abundantly expressed in articular cartilage. Here, the authors show that in mice, loss of Wwp2 leads to upregulated Runx2-Adamts5 signaling in articular cartilage and development of osteoarthritis, and that disease severity is reduced by injection of Wwp2 mRNA
- Sho Mokuda
- , Ryo Nakamichi
- & Hiroshi Asahara
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Article
| Open AccessGWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures
Size and shape of bones are important for height and body shape. Here, Styrkarsdottir et al identify 12 loci in a GWAS for bone area derived from DXA scans and show that these loci associate with other bone-related phenotypes including osteoarthritis, height, bone mineral density and risk of hip fracture.
- Unnur Styrkarsdottir
- , Olafur A. Stefansson
- & Kari Stefansson
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Article
| Open AccessCXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis
CXCL4 is an inflammatory chemokine signaling through CXCR3 receptor. Here the authors show a CXCR3-independent function of CXCL4: it forms liquid crystals with DNA, potentiating mammalian and bacterial DNA recognition by TLR9, thereby amplifying interferon-a production in systemic sclerosis.
- Roberto Lande
- , Ernest Y. Lee
- & Loredana Frasca
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Article
| Open AccessA small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development
Loss of cartilage tissue is a hallmark of osteoarthritis. Here the authors show that BNTA, a small molecule identified in a chemical screen, promotes ECM generation in human osteoarthritic chondrocytes and cartilage explants, and suppresses pathology in a rat model of osteoarthritis.
- Yuanyuan Shi
- , Xiaoqing Hu
- & Yingfang Ao
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Article
| Open AccessAdenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome
Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.
- Ramadan A. Ali
- , Alex A. Gandhi
- & Jason S. Knight