Rheumatology

  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    The suture mesenchyme has been postulated to act as the niche for stem cells for calvarial bones but the identity of the stem cells is unknown. Here, Maruyama et al.suggest that Axin2 expressing cells act as stem cells not only in craniofacial bone development and homeostasis but in injury-induced repair.

    • Takamitsu Maruyama
    • , Jaeim Jeong
    •  & Wei Hsu
  • Article
    | Open Access

    The transcriptional regulators E2F/Dp play a critical role in cell-cycle regulation, but it is unclear why E2F-deficient flies die. Here, the authors show this is linked to the function of E2F in adult Drosophilaskeletal muscle, with the contribution of E2f1 being most important in post-fusion muscle.

    • Maria Paula Zappia
    •  & Maxim V. Frolov
  • Article
    | Open Access

    PGC-1 family transcription factors are important regulators of cellular energy metabolism. Here the authors use tissue-specific, inducible PGC-1β KO mice to show that PGC-1 family members are not functionally redundant and that PGC-1β is required to maintain mitochondrial function in skeletal muscle.

    • Thanuja Gali Ramamoorthy
    • , Gilles Laverny
    •  & Daniel Metzger
  • Article |

    Long intervening noncoding RNAs (lincRNAs) are an emerging class of molecular regulators with diverse functions. Here the authors identify Linc-YY1, a novel lincRNA transcribed from the noncoding region of the mouse YY1 gene, that binds to YY1 protein and thereby regulates skeletal muscle differentiation and regeneration.

    • Liang Zhou
    • , Kun Sun
    •  & Huating Wang
  • Article
    | Open Access

    TAK1 is a MEK kinase family member that activates pro-survival NF-kB signalling but also pro-apoptotic caspase signalling in various cell types. Here the authors show that satellite-cell specific deletion of TAK1 in mice depletes the muscle stem cell pool and thus limits myofibre regeneration after injury.

    • Yuji Ogura
    • , Sajedah M. Hindi
    •  & Ashok Kumar
  • Article
    | Open Access

    Nerve damage can lead to skeletal muscle paralysis and atrophy. Here, the authors show that localized photostimulation of mouse calf muscle expressing the light-sensitive channel Channelrhodopsin-2 generates contraction in the absence of neural impulses and prove that this strategy can be used to prevent muscle atrophy.

    • Philippe Magown
    • , Basavaraj Shettar
    •  & Victor F. Rafuse
  • Article
    | Open Access

    The transcriptional regulator Tbx15 has a role in organ development. Here Lee et al.show that Tbx15 influences fibre-type determination in murine skeletal muscles, explaining local and systemic metabolic derangements in heterozygous Tbx15 knockout mice.

    • Kevin Y. Lee
    • , Manvendra K. Singh
    •  & C. Ronald Kahn
  • Article
    | Open Access

    Newts can regenerate amputated limbs via unknown mechanism involving dedifferentiation of cells in the stump into progenitors that contribute to the new appendages. Here the authors show that skeletal muscle dedifferentiation in regenerating newt limbs relies on a diverted programmed cell death response by myofibers.

    • Heng Wang
    • , Sara Lööf
    •  & András Simon
  • Article |

    Skeletal muscle satellite cells are muscle stem cells believed to contribute only to regenerating myofibres. Here Keefe et al. show that in adult sedentary mice satellite cells continue to fuse with uninjured myofibres, but they are not globally required for the maintenance of aging muscles.

    • Alexandra C. Keefe
    • , Jennifer A. Lawson
    •  & Gabrielle Kardon