Featured
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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 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 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 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 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 AccessGenome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density
GWAS have identified numerous genetic loci for bone mineral density (BMD) and fracture risk. Here, the authors map these variants to putative target genes using ATAC-seq and Capture C of human osteoblasts and confirm ING3 and EPDR1 as BMD genes in in vitro osteoblast differentiation experiments.
- Alessandra Chesi
- , Yadav Wagley
- & Struan F. A. Grant
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Article
| Open AccessNoninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis
Modulation of the cholinergic pathway and spleen function can reduce inflammation with invasive implants. Here, the authors show that non-invasive ultrasound stimulation of the spleen reduces disease severity in a mouse model of inflammatory arthritis, partly via altering B and T cell function.
- Daniel P. Zachs
- , Sarah J. Offutt
- & Hubert H. Lim
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Article
| Open AccessThe cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells
Metabolic pathways are increasingly recognized as crucial determinants of T cell function. Here the authors show that the balance between IFNγ and IL-10 production in human CD4 T cells is modulated by the cholesterol biosynthetic pathway.
- Esperanza Perucha
- , Rossella Melchiotti
- & Andrew P. Cope
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Article
| Open AccessProstaglandin E2 mediates sensory nerve regulation of bone homeostasis
Bone is innervated, and its turnover is affected by sympathetic nerve activity. Here, the authors show that prostaglandin E2, secreted by osteoblasts, activates the EP4 receptor on sensory nerves, inhibiting sympathetic nerve activity and modulating bone formation in mice.
- Hao Chen
- , Bo Hu
- & Xu Cao
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Article
| Open AccessRORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients
The role of innate T cell subsets in the pathogenesis of spondyloarthritis (SpA) is not well understood. Here, the authors examine the role of invariant natural killer T (iNKT) and γδ-T cells in SpA and show that disease-derived iNKT and γδ-T cells have unique and Th17-skewed phenotype and gene expression profiles within inflamed joints.
- Koen Venken
- , Peggy Jacques
- & Dirk Elewaut
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Article
| Open AccessMechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis
Pro-inflammatory factors implicated for the onset of arthritis often have systematic effects, yet arthritis symptoms are mostly limited to the joints. Here the authors show that mechanical strain at the joints promotes the recruitment of monocyte and their differentiation into bone-eroding osteoclast to contribute this tissue specificity.
- Isabelle Cambré
- , Djoere Gaublomme
- & Dirk Elewaut
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Article
| Open AccessCationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation
Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here the authors use ~40 nm cationic nanoparticles to scavenge cfDNA, and demonstrate the potential for nanomedicine to relieve debilitating RA symptoms.
- Huiyi Liang
- , Bo Peng
- & Yongming Chen
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Article
| Open AccessGenetic signature to provide robust risk assessment of psoriatic arthritis development in psoriasis patients
Approximately 30% of psoriasis patients develop psoriatic arthritis (PsA) and early diagnosis is crucial for the management of PsA. Here, Patrick et al. develop a computational pipeline involving statistical and machine-learning methods that can assess the risk of progression to PsA based on genetic markers.
- Matthew T. Patrick
- , Philip E. Stuart
- & Lam C. Tsoi
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Article
| Open AccessBone protection by inhibition of microRNA-182
Osteoclasts mediate bone disruption in a number of degenerative bone diseases. Here, the authors show that miR-182 regulates osteoclastogenesis via PKR and IFN-beta signaling, is correlated with rheumatoid arthritis, and that its ablation or inhibition is protective against bone erosion in mouse models of osteoporosis or inflammatory arthritis.
- Kazuki Inoue
- , Zhonghao Deng
- & Baohong Zhao
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Review Article
| Open AccessResolution of chronic inflammatory disease: universal and tissue-specific concepts
Inflammation is a component of many chronic inflammatory diseases and yet it is understudied in medicine. Here, the authors review novel insights in to inflammation and how impairment of its resolution can lead to diseases.
- Georg Schett
- & Markus F. Neurath
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Correspondence
| Open AccessReply to ‘Trace N-glycans including sulphated species may originate from various plasma glycoproteins and not necessarily IgG’
- Jing-Rong Wang
- , Wei-Na Gao
- & Zhi-Hong Jiang
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Article
| Open AccessOsteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin
Osteocytes reside in a low oxygen environment, but it is not clear if oxygen sensing regulates their function. Here, the authors show that deletion of the oxygen sensor prolyl hydroxylase 2 in osteocytes leads to increased bone mass via regulation of sclerostin, and reduces bone loss in mouse models of osteoporosis.
- Steve Stegen
- , Ingrid Stockmans
- & Geert Carmeliet
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Article
| Open AccessC-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease
IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis.
- Antoine Dufour
- , Caroline L. Bellac
- & Christopher M. Overall
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Article
| Open AccessA multi-modal MRI study of the central response to inflammation in rheumatoid arthritis
Many diseases, such as rheumatoid arthritis, are characterized by a chronic inflammatory state, but it is not clear whether or how this affects the brain. Here, the authors show that the severity of on-going inflammation predicts altered functional brain connectivity in people with rheumatoid arthritis.
- Andrew Schrepf
- , Chelsea M. Kaplan
- & Neil Basu
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Article
| Open AccessComprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes
Fibroblast-like synoviocytes (FLS) in the intimal layer of the synovium can become invasive and destroy cartilage in patients with rheumatoid arthritis (RA). Here the authors integrate a variety of epigenomic data to map the epigenome of FLS in RA and identify potential therapeutic targets.
- Rizi Ai
- , Teresina Laragione
- & Gary S. Firestein
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Article
| Open AccessDirected evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
CXCR2 antagonism has been shown to be anti-arthritic, but anti-chemokine therapies usually fail in the clinic owing to redundancy in chemokine-receptor interactions. Here the authors develop single-chain antibodies with multiple chemokine specificities to achieve high affinity and broad specificity to mouse and human CXC chemokines with efficacy in a K/BxN serum transfer model of arthritis.
- Alessandro Angelini
- , Yoshishige Miyabe
- & K. Dane Wittrup
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Article
| Open AccessSmall tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
Anti-TNF therapy has improved the treatment of inflammatory disease but can predispose to infection and malignancy. Here the authors show an anti-TNF biologic peptide that functionally and selectively targets the TNF-p38 pathway in multiple models of inflammation.
- Violet R. Mukaro
- , Alex Quach
- & Antonio Ferrante
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Article
| Open AccessTowards an arthritis flare-responsive drug delivery system
The treatment of inflammatory arthritis by local delivery of therapeutics is limited by short half-lives of drugs. Here the authors demonstrate a hydrogel platform that titrates drug release to arthritis activity.
- Nitin Joshi
- , Jing Yan
- & Jeffrey M. Karp
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Article
| Open AccessFunctionally distinct disease-associated fibroblast subsets in rheumatoid arthritis
Synovial fibroblasts are thought to be central mediators of joint destruction in rheumatoid arthritis (RA). Here the authors use single-cell transcriptomics and flow cytometry to identify synovial fibroblast subsets that are expanded and display distinct tissue distribution and function in patients with RA.
- Fumitaka Mizoguchi
- , Kamil Slowikowski
- & Michael B. Brenner
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Article
| Open AccessThe p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts
TNF is a major therapeutic target for rheumatoid arthritis (RA) and synovial fibroblasts are central to the pathogenesis of RA. Here the authors dissect TNF-induced death and activation signalling in RA synovial fibroblasts and TNF-driven arthritis and indicate that a successful therapeutic strategy might be to target both IKK2 and RIPK3 at the same time.
- Marietta Armaka
- , Caroline Ospelt
- & George Kollias
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Article
| Open AccessIL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation
Th17 cells are a common pathogenic effector cell in autoimmune inflammatory diseases. Here the authors show that the transcription factor RFX1 limits Th17 differentiation and is protective against the pathogenesis of Th17-driven autoimmune diseases.
- Ming Zhao
- , Yixin Tan
- & Qianjin Lu
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Article
| Open AccessDJ-1 controls bone homeostasis through the regulation of osteoclast differentiation
Osteoclasts are involved in arthritis, and their differentiation depends on RANKL signaling. The author show that the ROS-scavenging protein DJ-1 negatively regulates RANKL signaling and that its ablation increases osteoclast numbers and exacerbates bone damage in mouse models of arthritis.
- Hyuk Soon Kim
- , Seung Taek Nam
- & Wahn Soo Choi
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Article
| Open AccessActivation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis
STAT3 is a transcription factor that is activated in fibrotic diseases such as systemic sclerosis. Here the authors show that STAT3 is the converging point for multiple pro-fibrotic signalling pathways, and that its genetic ablation or inhibition ameliorate skin fibrosis in mouse models.
- Debomita Chakraborty
- , Barbora Šumová
- & Jörg H. W. Distler
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Article
| Open AccessA method to identify trace sulfated IgG N-glycans as biomarkers for rheumatoid arthritis
Post-translational modifications can affect antibody function in health and disease, but identification of all variants is difficult using existing technologies. Here the authors develop a microfluidic method to identify and quantify low-abundance IgG N-glycans and show some of these IgGs can be used as biomarkers for rheumatoid arthritis.
- Jing-Rong Wang
- , Wei-Na Gao
- & Zhi-Hong Jiang
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Article
| Open AccessSomatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis
Accumulation of somatic mutations in lymphocytes is a feature of some cancers. Here the authors show that patients with recent onset of rheumatoid arthritis also accumulate mutations in their expanded CD8+ effector memory T cell pool independent of cancer association.
- P. Savola
- , T. Kelkka
- & S. Mustjoki
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Article
| Open AccessDOT1L safeguards cartilage homeostasis and protects against osteoarthritis
DOT1L is one of the few genes linked to osteoarthritis by human GWAS. Here the authors show that DOT1L-dependent histone methylation protects homeostasis of articular chondrocytes by SIRT1-dependent inhibition of canonical WNT signalling, and that inhibition of DOT1L can drive osteoarthritic disease in mice.
- Silvia Monteagudo
- , Frederique M. F. Cornelis
- & Rik J. Lories
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Article
| Open AccessSuccinate and its G-protein-coupled receptor stimulates osteoclastogenesis
Bone loss is common in patients with diabetes, but the underlying molecular and cellular mechanisms are unclear. Here the authors show high succinate levels in mice with type 2 diabetes and that succinate can signal through succinate receptor 1 on osteoclasts to induce bone resorption.
- Yuqi Guo
- , Chengzhi Xie
- & Xin Li
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Article
| Open AccessJoint morphogenetic cells in the adult mammalian synovium
The stem cells that maintain and repair adult joint tissues in mammals, including articular cartilage, remain incompletely defined. Here the authors perform lineage tracing studies in adult mice and find an ontogenetically defined progenitor cell population that is functional in the synovial joint and distinct from previously reported mesenchymal stem cell populations.
- Anke J. Roelofs
- , Janja Zupan
- & Cosimo De Bari
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Article
| Open AccessEndogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression
Osteoarthritis (OA) is a debilitating and destructive joint disease for which disease modifying drugs are not available. Here the authors show that extracellular adenosine signalling via the A2AR receptor on chondrocytes is needed to prevent OA and that liposome-bound adenosine injection can treat the pathology in rats.
- Carmen Corciulo
- , Matin Lendhey
- & Bruce N. Cronstein
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Article
| Open AccessSequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation
Lumbar disc herniation (LDH) can cause persistent sciatica, and in some cases surgery is required to relieve symptoms. Here, the authors carry out a genome-wide association study using microdiscectomy as an indicator of severe LDH, and find a locus on chromosome 8 associated with this condition.
- Gyda Bjornsdottir
- , Stefania Benonisdottir
- & Kari Stefansson
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Article
| Open AccessDEK-targeting DNA aptamers as therapeutics for inflammatory arthritis
DEK is a secreted protein abundant in the synovia of patients with juvenile idiopathic arthritis. Here the authors show DEK is important for neutrophil extracellular trap formation and joint inflammation, and demonstrate therapeutic efficacy of DEK-targeting aptamers in a mouse model of arthritis.
- Nirit Mor-Vaknin
- , Anjan Saha
- & David M. Markovitz
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Article
| Open AccessPten is necessary for the quiescence and maintenance of adult muscle stem cells
Pten is known to regulate haematopoietic stem cell functions. Here the authors show that Ptenalteration of Notch signalling has stage-specific muscle regenerative functions in muscle stem cells by preventing premature differentiation of quiescent cells and enhancing the self-renewal of activated cells.
- Feng Yue
- , Pengpeng Bi
- & Shihuan Kuang
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Article
| Open AccessExploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury
A potentially superior tissue regenerative strategy to stem cell transplantation is modulation of endogenous stem cells. Here the authors show fibrocartilage stem cells exist in the temporomandibular joint that contribute to cartilage regeneration and can be manipulated to enhance regeneration through canonical Wnt signalling.
- Mildred C. Embree
- , Mo Chen
- & Jeremy J. Mao
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Article
| Open AccessMicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis
MiR-155 is thought to inhibit PU.1 and thereby drive antigen-induced B-cell maturation. Here the authors show that patients with rheumatoid arthritis have high B-cell miR-155 expression and that an antagomir can rescue PU.1 expression, suggesting potential therapeutic avenues to treat rheumatoid arthritis.
- Stefano Alivernini
- , Mariola Kurowska-Stolarska
- & Gianfranco Ferraccioli
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Article
| Open AccessMRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity
Mrf4 is a transcription factor important for muscle development, but despite high expression its function in adults is unknown. Here the authors show that interfering with Mrf4 in adult mice leads to muscle hypertrophy by activating MEF2-dependent transcription and promoting protein synthesis.
- Irene Moretti
- , Stefano Ciciliot
- & Stefano Schiaffino
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Article
| Open AccessThe genetic regulatory signature of type 2 diabetes in human skeletal muscle
More than 90% of genetic variants associated with type 2 diabetes occur in non-coding regions. Scott et al. report genomes, epigenomes and transcriptomes of skeletal muscle from 271 participants with a range of glucose tolerances, revealing a genetic regulatory architecture enriched in muscle stretch/super enhancers.
- Laura J. Scott
- , Michael R. Erdos
- & Stephen C. J. Parker
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Article
| Open AccessPterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3
Therapies are needed for the prevention of chondrocyte hypertrophy and thinning of articular cartilage, features of osteoarthritic joint destruction. Here, the authors show that interfering with Sik3 signalling can increase the size of the chondrocyte population and reduce severity of a surgically induced mouse model of osteoarthritis.
- Yasuhito Yahara
- , Hiroshi Takemori
- & Noriyuki Tsumaki
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Article
| Open AccessHexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
Exon-skipping therapies such as systemic i.v. administration of morpholino are being explored as a means of treating Duchenne muscular dystrophy. Here the authors show that adding a glucose-fructose mix can enhance uptake of phosphorodiamidate morpholino oligomer and its therapeutic effect in mdxmice.
- Gang Han
- , Ben Gu
- & HaiFang Yin