Rheumatology

  • Article
    | Open Access

    Spinal pain is a major clinical problem. Here the authors show that osteoclasts create porous area of endplates of the vertebrae and sensory innervation of porous endplates by Netrin-1 release from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.

    • Shuangfei Ni
    • , Zemin Ling
    • , Xiao Wang
    • , Yong Cao
    • , Tianding Wu
    • , Ruoxian Deng
    • , Janet L. Crane
    • , Richard Skolask
    • , Shadpour Demehril
    • , Gehua Zhen
    • , Amit Jain
    • , Panfeng Wu
    • , Dayu Pan
    • , Bo Hu
    • , Xiao Lyu
    • , Yusheng Li
    • , Hao Chen
    • , Huabin Qi
    • , Yun Guan
    • , Xinzhong Dong
    • , Mei Wan
    • , Xuenong Zou
    • , Hongbin Lu
    • , Jianzhong Hu
    •  & Xu Cao
  • Article
    | Open Access

    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
    • , Pei-Chien Tsai
    • , Susanna Roberts
    • , Rosa Andres-Ejarque
    • , Stefano Nardone
    • , Jordana T. Bell
    • , Chloe C. Y. Wong
    •  & Kerrin S. Small
  • Article
    | Open Access

    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
    • , Federico Alberici
    • , James Liley
    • , Richard M. R. Coulson
    • , William Astle
    • , Chiara Baldini
    • , Francesco Bonatti
    • , Maria C Cid
    • , Heather Elding
    • , Giacomo Emmi
    • , Jörg Epplen
    • , Loïc Guillevin
    • , David R. W. Jayne
    • , Tao Jiang
    • , Iva Gunnarsson
    • , Peter Lamprecht
    • , Stephen Leslie
    • , Mark A. Little
    • , Davide Martorana
    • , Frank Moosig
    • , Thomas Neumann
    • , Sophie Ohlsson
    • , Stefanie Quickert
    • , Giuseppe A. Ramirez
    • , Barbara Rewerska
    • , Georg Schett
    • , Renato A. Sinico
    • , Wojciech Szczeklik
    • , Vladimir Tesar
    • , Damjan Vukcevic
    • , Mohammed Akil
    • , Jonathan Barratt
    • , Neil Basu
    • , Adam S. Butterworth
    • , Ian Bruce
    • , Michael Clarkson
    • , Niall Conlon
    • , Bhaskar DasGupta
    • , Timothy W. R. Doulton
    • , Georgina Espígol-Frigolé
    • , Oliver Flossmann
    • , Armando Gabrielli
    • , Jolanta Gasior
    • , Gina Gregorini
    • , Giuseppe Guida
    • , José Hernández-Rodríguez
    • , Zdenka Hruskova
    • , Amy Hudson
    • , Ann Knight
    • , Peter Lanyon
    • , Raashid Luqmani
    • , Malgorzata Magliano
    • , Angelo A. Manfredi
    • , Christopher Marguerie
    • , Federica Maritati
    • , Chiara Marvisi
    • , Neil J. McHugh
    • , Eamonn Molloy
    • , Allan Motyer
    • , Chetan Mukhtyar
    • , Leonid Padyukov
    • , Alberto Pesci
    • , Sergio Prieto-Gonzalez
    • , Marc Ramentol-Sintas
    • , Petra Reis
    • , Dario Roccatello
    • , Patrizia Rovere-Querini
    • , Carlo Salvarani
    • , Francesca Santarsia
    • , Roser Solans-Laque
    • , Nicole Soranzo
    • , Jo Taylor
    • , Julie Wessels
    • , Jochen Zwerina
    • , Benjamin Terrier
    • , Richard A Watts
    • , Augusto Vaglio
    • , Julia U Holle
    • , Chris Wallace
    •  & Kenneth G. C. Smith
  • Article
    | Open Access

    During high-intensity exercise, muscles convert glucose to lactate, in a process that is energetically less efficient than respiration. Here the authors develop a computational model based on muscle proteomic data showing that bypassing mitochondrial complex I increases ATP production rates, and validate these model predictions in an exercise test on 5 subjects.

    • Avlant Nilsson
    • , Elias Björnson
    • , Mikael Flockhart
    • , Filip J. Larsen
    •  & Jens Nielsen
  • Article
    | Open Access

    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
    • , Martin Kerick
    • , Shervin Assassi
    • , Ansuman T. Satpathy
    • , Jeffrey Granja
    • , Maxwell R. Mumbach
    • , Lorenzo Beretta
    • , Carmen P. Simeón
    • , Patricia Carreira
    • , Norberto Ortego-Centeno
    • , Ivan Castellvi
    • , Lara Bossini-Castillo
    • , F. David Carmona
    • , Gisela Orozco
    • , Nicolas Hunzelmann
    • , Jörg H. W. Distler
    • , Andre Franke
    • , Claudio Lunardi
    • , Gianluca Moroncini
    • , Armando Gabrielli
    • , Jeska de Vries-Bouwstra
    • , Cisca Wijmenga
    • , Bobby P. C. Koeleman
    • , Annika Nordin
    • , Leonid Padyukov
    • , Anna-Maria Hoffmann-Vold
    • , Benedicte Lie
    • , R. Ríos
    • , J. L. Callejas
    • , J. A. Vargas-Hitos
    • , R. García-Portales
    • , M. T. Camps
    • , A. Fernández-Nebro
    • , M. F. González-Escribano
    • , F. J. García-Hernández
    • , M. J. Castillo
    • , M. A. Aguirre
    • , I. Gómez-Gracia
    • , B. Fernández-Gutiérrez
    • , L. Rodríguez-Rodríguez
    • , P. García de la Peña
    • , E. Vicente
    • , J. L. Andreu
    • , M Fernández de Castro
    • , F. J. López-Longo
    • , L. Martínez
    • , Fonollosa V
    • , A. Guillén
    • , G. Espinosa
    • , C. Tolosa
    • , A. Pros
    • , M. Rodríguez-Carballeira
    • , F. J. Narváez
    • , M. Rubio-Rivas
    • , Ortiz-Santamaría V
    • , A. B. Madroñero
    • , M. A. González-Gay
    • , B. Díaz
    • , L. Trapiella
    • , A. Sousa
    • , M. V. Egurbide
    • , P. Fanlo-Mateo
    • , L. Sáez-Comet
    • , F. Díaz
    • , Hernández V
    • , E. Beltrán
    • , J. A. Román-Ivorra
    • , E. Grau
    • , J. J. Alegre-Sancho
    • , M. Freire
    • , F. J. Blanco-García
    • , N. Oreiro
    • , T. Witte
    • , A. Kreuter
    • , G. Riemekasten
    • , P. Airó
    • , C. Magro
    • , A. E. Voskuyl
    • , M. C. Vonk
    • , R. Hesselstrand
    • , Susanna Proudman
    • , Wendy Stevens
    • , Mandana Nikpour
    • , J. Zochling
    • , J. Sahhar
    • , J. Roddy
    • , P. Nash
    • , K. Tymms
    • , M. Rischmueller
    • , S. Lester
    • , Timothy Vyse
    • , Ariane L. Herrick
    • , Jane Worthington
    • , Christopher P. Denton
    • , Yannick Allanore
    • , Matthew A. Brown
    • , Timothy R. D. J. Radstake
    • , Carmen Fonseca
    • , Howard Y. Chang
    • , Maureen D. Mayes
    •  & Javier Martin
  • Article
    | Open Access

    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
    • , Yeongjae Kim
    • , Hyeon-Seop Kim
    • , Young-Ran Gu
    • , Donghyun Kang
    • , Yongsik Cho
    • , Hyeonkyeong Kim
    • , Jeeyeon Lee
    • , Yeyoung Seo
    • , Moon Jong Chang
    • , Chong Bum Chang
    • , Seung-Baik Kang
    •  & Jin-Hong Kim
  • Article
    | Open Access

    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
    • , Carolina Medina-Gomez
    • , Sanzhima Garmaeva
    • , Dieuwke Schiphof
    • , Pascal Arp
    • , Thomas Koet
    • , Alexander Kurilshikov
    • , Jingyuan Fu
    • , M. Arfan Ikram
    • , Sita Bierma-Zeinstra
    • , André G. Uitterlinden
    • , Robert Kraaij
    • , Alexandra Zhernakova
    •  & Joyce B. J. van Meurs
  • Article
    | Open Access

    Reactive oxygen species (ROS) stimulate GLUT4-mediated glucose transport following contraction of isolated muscle, but it is not clear if this occurs in vivo. Here, the authors show in human volunteers that exercise induces ROS increase in muscle and, using loss of-function animal models, they demonstrate that NOX2 is a major ROS source required to stimulate glucose uptake during exercise.

    • Carlos Henríquez-Olguin
    • , Jonas R. Knudsen
    • , Steffen H. Raun
    • , Zhencheng Li
    • , Emilie Dalbram
    • , Jonas T. Treebak
    • , Lykke Sylow
    • , Rikard Holmdahl
    • , Erik A. Richter
    • , Enrique Jaimovich
    •  & Thomas E. Jensen
  • Article
    | Open Access

    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
    • , Chelsea A. Taylor
    • , Evelyn Lau
    • , Sara Danielli
    • , Jelle de Wit
    • , James Gilchrist
    • , Isar Nassiri
    • , Elise A. Mahe
    • , Wanseon Lee
    • , Laila Rizvi
    • , Seiko Makino
    • , Jane Cheeseman
    • , Matt Neville
    • , Julian C. Knight
    • , Paul Bowness
    •  & Benjamin P. Fairfax
  • Article
    | Open Access

    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
    • , Cheng Lu
    • , Duoli Xie
    • , Jin Liu
    • , Chuanxin Zhong
    • , Xiaohao Wu
    • , Rongchen Dai
    • , Huarui Zhang
    • , Daogang Guan
    • , Baosheng Guo
    • , Bing He
    • , Fangfei Li
    • , Xiaojuan He
    • , Wandong Zhang
    • , Bao-Ting Zhang
    • , Ge Zhang
    •  & Aiping Lu
  • Article
    | Open Access

    Multiple myeloma is a cancer of the bone marrow that can induce bone disease. Here, the authors profile the transcriptome of bone-lining cells and find a targetable role of bone morphogenetic protein (BMP) signalling in myeloma-induced bone-disease

    • Sarah Gooding
    • , Sam W. Z. Olechnowicz
    • , Emma V. Morris
    • , Andrew E. Armitage
    • , Joao Arezes
    • , Joe Frost
    • , Emmanouela Repapi
    • , James R. Edwards
    • , Neil Ashley
    • , Craig Waugh
    • , Nicola Gray
    • , Erik Martinez-Hackert
    • , Pei Jin Lim
    • , Sant-Rayn Pasricha
    • , Helen Knowles
    • , Adam J. Mead
    • , Karthik Ramasamy
    • , Hal Drakesmith
    •  & Claire M. Edwards
  • Article
    | Open Access

    HuR is an RNA-binding protein that regulates myotube differentiation in vitro. Here, the authors show that the muscle-specific ablation of HuR in mice leads to enhanced endurance capacity and an increase in oxidative fibres by destabilising PGC1α-mRNA, and show that the mice are protected against cancer cachexia

    • Brenda Janice Sánchez
    • , Anne-Marie K. Tremblay
    • , Jean-Philippe Leduc-Gaudet
    • , Derek T. Hall
    • , Erzsebet Kovacs
    • , Jennifer F. Ma
    • , Souad Mubaid
    • , Patricia L. Hallauer
    • , Brittany L. Phillips
    • , Katherine E. Vest
    • , Anita H. Corbett
    • , Dimitris L. Kontoyiannis
    • , Sabah N. A. Hussain
    • , Kenneth E. M. Hastings
    • , Sergio Di Marco
    •  & Imed-Eddine Gallouzi
  • Article
    | Open Access

    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
    • , Joanne Nititham
    • , Kimberly E. Taylor
    • , Milena Gianfrancesco
    • , Manish Paranjpe
    • , Shan Andrews
    • , Sharon A. Chung
    • , Brooke Rhead
    • , Lisa F. Barcellos
    • , Laura Trupin
    • , Patricia Katz
    • , Maria Dall’Era
    • , Jinoos Yazdany
    • , Marina Sirota
    •  & Lindsey A. Criswell
  • Article
    | Open Access

    Adolescent idiopathic scoliosis (AIS) is a common pediatric disease leading to spinal deformities. Here, the authors report GWAS followed by genome-wide meta-analysis in up to 79,211 Japanese individuals, identifying 20 genetic loci for AIS, 14 of which were previously unreported, and perform in vitro validation for rs1978060.

    • Ikuyo Kou
    • , Nao Otomo
    • , Kazuki Takeda
    • , Yukihide Momozawa
    • , Hsing-Fang Lu
    • , Michiaki Kubo
    • , Yoichiro Kamatani
    • , Yoji Ogura
    • , Yohei Takahashi
    • , Masahiro Nakajima
    • , Shohei Minami
    • , Koki Uno
    • , Noriaki Kawakami
    • , Manabu Ito
    • , Ikuho Yonezawa
    • , Kei Watanabe
    • , Takashi Kaito
    • , Haruhisa Yanagida
    • , Hiroshi Taneichi
    • , Katsumi Harimaya
    • , Yuki Taniguchi
    • , Hideki Shigematsu
    • , Takahiro Iida
    • , Satoru Demura
    • , Ryo Sugawara
    • , Nobuyuki Fujita
    • , Mitsuru Yagi
    • , Eijiro Okada
    • , Naobumi Hosogane
    • , Katsuki Kono
    • , Masaya Nakamura
    • , Kazuhiro Chiba
    • , Toshiaki Kotani
    • , Tsuyoshi Sakuma
    • , Tsutomu Akazawa
    • , Teppei Suzuki
    • , Kotaro Nishida
    • , Kenichiro Kakutani
    • , Taichi Tsuji
    • , Hideki Sudo
    • , Akira Iwata
    • , Tatsuya Sato
    • , Satoshi Inami
    • , Morio Matsumoto
    • , Chikashi Terao
    • , Kota Watanabe
    •  & Shiro Ikegawa
  • Article
    | Open Access

    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
    • , Peter J. Eggenhuizen
    • , Ling L. Chua
    • , Mirjan van Timmeren
    • , Khai L. Loh
    • , Kim M. O’Sullivan
    • , Poh Y. Gan
    • , Yong Zhong
    • , Kirill Tsyganov
    • , Lani R. Shochet
    • , Jessica Ryan
    • , Coen A. Stegeman
    • , Lars Fugger
    • , Hugh H. Reid
    • , Jamie Rossjohn
    • , Peter Heeringa
    • , Stephen R. Holdsworth
    • , Anton Y. Peleg
    •  & A. Richard Kitching
  • Article
    | Open Access

    Denervation leads to muscle atrophy and neuromuscular endplate remodeling. Here, the authors show that a balanced activation of mTORC1 contributes to the dynamic regulation of autophagic flux in denervated muscle and that activation of PKB/Akt promotes the nuclear import of HDAC4, which is essential for endplate maintenance upon nerve injury

    • Perrine Castets
    • , Nathalie Rion
    • , Marine Théodore
    • , Denis Falcetta
    • , Shuo Lin
    • , Markus Reischl
    • , Franziska Wild
    • , Laurent Guérard
    • , Christopher Eickhorst
    • , Marielle Brockhoff
    • , Maitea Guridi
    • , Chikwendu Ibebunjo
    • , Joseph Cruz
    • , Michael Sinnreich
    • , Rüdiger Rudolf
    • , David J. Glass
    •  & Markus A. Rüegg
  • Article
    | Open Access

    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
    • , Dan Wang
    • , Jung-Min Kim
    • , Phillip W. L. Tai
    • , Ellen Gravallese
    • , Guangping Gao
    •  & Jae-Hyuck Shim
  • Article
    | Open Access

    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
    • , Yunshan Fan
    • , Lifan Liao
    • , Peter X. Ma
    • , Guozhi Xiao
    •  & Di Chen
  • Article
    | Open Access

    Bone regeneration is of interest for treating a wide range of medical conditions. Here, the authors report on bioinspired matrix vesicles loaded with black phosphorus nanosheets and cell-specific aptamers for bone regeneration and demonstrate bone defect repair in vivo.

    • Yingqian Wang
    • , Xiaoxia Hu
    • , Lingling Zhang
    • , Chunli Zhu
    • , Jie Wang
    • , Yingxue Li
    • , Yulan Wang
    • , Can Wang
    • , Yufeng Zhang
    •  & Quan Yuan
  • Article
    | Open Access

    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
    • , Yan Xiu
    • , Xiaoxiang Yin
    • , James O. Sanders
    • , Addisu Mesfin
    • , Lianping Xing
    • , Zhenqiang Yao
    •  & Brendan F. Boyce
  • Article
    | Open Access

    A number of therapeutic agents aimed at reducing pathology in Duchenne muscular dystrophy have been developed, but may have off-target effects when delivered systemically. Here, the authors express the therapeutic LIF transgene in leukocytes, and show this results in targeting to inflamed dystrophic muscle and reduced fibrosis by suppressing type 2 immunity.

    • Steven S. Welc
    • , Ivan Flores
    • , Michelle Wehling-Henricks
    • , Julian Ramos
    • , Ying Wang
    • , Carmen Bertoni
    •  & James G. Tidball
  • Article
    | Open Access

    In vivo decorporation of U(VI) from bones is an unsolved challenge because of the formation of stable uranium phosphate complexes. Here, the authors develop a hydroxypyridonone-based ligand with strong uranium complexation and low cytotoxicity. They find this ligand effectively removes uranium from kidney and bones in mice, and is suitable for oral administration.

    • Xiaomei Wang
    • , Xing Dai
    • , Cen Shi
    • , Jianmei Wan
    • , Mark A. Silver
    • , Linjuan Zhang
    • , Lanhua Chen
    • , Xuan Yi
    • , Bizheng Chen
    • , Duo Zhang
    • , Kai Yang
    • , Juan Diwu
    • , Jianqiang Wang
    • , Yujie Xu
    • , Ruhong Zhou
    • , Zhifang Chai
    •  & Shuao Wang
  • Article
    | Open Access

    Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca2+ homeostasis and cellular stress responses.

    • Giulia Favaro
    • , Vanina Romanello
    • , Tatiana Varanita
    • , Maria Andrea Desbats
    • , Valeria Morbidoni
    • , Caterina Tezze
    • , Mattia Albiero
    • , Marta Canato
    • , Gaia Gherardi
    • , Diego De Stefani
    • , Cristina Mammucari
    • , Bert Blaauw
    • , Simona Boncompagni
    • , Feliciano Protasi
    • , Carlo Reggiani
    • , Luca Scorrano
    • , Leonardo Salviati
    •  & Marco Sandri
  • Article
    | Open Access

    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
    • , Dandan Wang
    • , Zhuoya Zhang
    • , Xiaojun Tang
    • , Xiang Gao
    • , Wanjun Chen
    •  & Lingyun Sun
  • Article
    | Open Access

    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
    • , Sarah J. Rice
    • , Colin Shepherd
    • , Vikram Agarwal
    • , John Loughlin
    •  & Jay Shendure
  • Article
    | Open Access

    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
    • , Tokio Matsuzaki
    • , Yoshiaki Ito
    • , Tempei Sato
    • , Kohei Miyata
    • , Masafumi Inui
    • , Merissa Olmer
    • , Eiji Sugiyama
    • , Martin Lotz
    •  & Hiroshi Asahara
  • Article
    | Open Access

    Function-altering variants of immune-related genes cause rare autoimmune syndromes, whereas their contribution to common autoimmune diseases remains uncharacterized. Here the authors show that rare variants of lupus-associated genes are present in the majority of lupus patients and healthy controls, but only the variants found in lupus patients alter gene function.

    • Simon H. Jiang
    • , Vicki Athanasopoulos
    • , Julia I. Ellyard
    • , Aaron Chuah
    • , Jean Cappello
    • , Amelia Cook
    • , Savit B. Prabhu
    • , Jacob Cardenas
    • , Jinghua Gu
    • , Maurice Stanley
    • , Jonathan A. Roco
    • , Ilenia Papa
    • , Mehmet Yabas
    • , Giles D. Walters
    • , Gaetan Burgio
    • , Kathryn McKeon
    • , James M. Byers
    • , Charlotte Burrin
    • , Anselm Enders
    • , Lisa A. Miosge
    • , Pablo F. Canete
    • , Marija Jelusic
    • , Velibor Tasic
    • , Adrian C. Lungu
    • , Stephen I. Alexander
    • , Arthur R. Kitching
    • , David A. Fulcher
    • , Nan Shen
    • , Todor Arsov
    • , Paul A. Gatenby
    • , Jeff J. Babon
    • , Dominic F. Mallon
    • , Carmen de Lucas Collantes
    • , Eric A. Stone
    • , Philip Wu
    • , Matthew A. Field
    • , Thomas D. Andrews
    • , Eun Cho
    • , Virginia Pascual
    • , Matthew C. Cook
    •  & Carola G. Vinuesa
  • Article
    | Open Access

    Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21, as IFN-responsive in immune cells that shows sexually dimorphic expression.

    • Christopher A. Odhams
    • , Amy L. Roberts
    • , Susan K. Vester
    • , Carolina S. T. Duarte
    • , Charlie T. Beales
    • , Alexander J. Clarke
    • , Sonja Lindinger
    • , Samuel J. Daffern
    • , Antonino Zito
    • , Lingyan Chen
    • , Leonardo L. Jones
    • , Lora Boteva
    • , David L. Morris
    • , Kerrin S. Small
    • , Michelle M. A. Fernando
    • , Deborah S. Cunninghame Graham
    •  & Timothy J. Vyse
  • Article
    | Open Access

    Arthroplasty is the main clinical option for the treatment of osteoarticular lesions, but has limited efficacy. Here, the authors use a wound dressing with autologous mesenchymal stromal cells, functionalised for local BMP2 delivery, and show feasibility and safety in standardised preclinical tests in animal models, suggesting suitability for use in clinical trials.

    • Laetitia Keller
    • , Luc Pijnenburg
    • , Ysia Idoux-Gillet
    • , Fabien Bornert
    • , Laila Benameur
    • , Maryam Tabrizian
    • , Pierrick Auvray
    • , Philippe Rosset
    • , Rosa María Gonzalo-Daganzo
    • , Enrique Gómez Barrena
    • , Luca Gentile
    •  & Nadia Benkirane-Jessel
  • Article
    | Open Access

    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
    • , Kristbjorg Gunnarsdottir
    • , Gudmar Thorleifsson
    • , Sigrun H. Lund
    • , Lilja Stefansdottir
    • , Kristinn Juliusson
    • , Arna B. Agustsdottir
    • , Florian Zink
    • , Gisli H. Halldorsson
    • , Erna V. Ivarsdottir
    • , Stefania Benonisdottir
    • , Hakon Jonsson
    • , Arnaldur Gylfason
    • , Kristjan Norland
    • , Katerina Trajanoska
    • , Cindy G. Boer
    • , Lorraine Southam
    • , Jason C. S. Leung
    • , Nelson L. S. Tang
    • , Timothy C. Y. Kwok
    • , Jenny S. W. Lee
    • , Suzanne C. Ho
    • , Inger Byrjalsen
    • , Jacqueline R. Center
    • , Seung Hun Lee
    • , Jung-Min Koh
    • , L. Stefan Lohmander
    • , Lan T. Ho-Pham
    • , Tuan V. Nguyen
    • , John A. Eisman
    • , Jean Woo
    • , Ping-C. Leung
    • , John Loughlin
    • , Eleftheria Zeggini
    • , Claus Christiansen
    • , Fernando Rivadeneira
    • , Joyce van Meurs
    • , Andre G. Uitterlinden
    • , Brynjolfur Mogensen
    • , Helgi Jonsson
    • , Thorvaldur Ingvarsson
    • , Gunnar Sigurdsson
    • , Rafn Benediktsson
    • , Patrick Sulem
    • , Ingileif Jonsdottir
    • , Gisli Masson
    • , Hilma Holm
    • , Gudmundur L. Norddahl
    • , Unnur Thorsteinsdottir
    • , Daniel F. Gudbjartsson
    •  & Kari Stefansson
  • Article
    | Open Access

    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
    • , Raffaella Palazzo
    • , Barbara Marinari
    • , Immacolata Pietraforte
    • , Giancarlo Santiago Santos
    • , Yves Mattenberger
    • , Francesca Spadaro
    • , Katia Stefanantoni
    • , Nicoletta Iannace
    • , Aleksandra Maria Dufour
    • , Mario Falchi
    • , Manuela Bianco
    • , Elisabetta Botti
    • , Luca Bianchi
    • , Montserrat Alvarez
    • , Valeria Riccieri
    • , Marie-Elise Truchetet
    • , Gerard C.L. Wong
    • , Carlo Chizzolini
    •  & Loredana Frasca
  • Article
    | Open Access

    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
    • , Jin Cheng
    • , Xin Zhang
    • , Fengyuan Zhao
    • , Weili Shi
    • , Bo Ren
    • , Huilei Yu
    • , Peng Yang
    • , Zong Li
    • , Qiang Liu
    • , Zhenlong Liu
    • , Xiaoning Duan
    • , Xin Fu
    • , Jiying Zhang
    • , Jianquan Wang
    •  & Yingfang Ao
  • Article
    | Open Access

    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
    • , He Meng
    • , Srilakshmi Yalavarthi
    • , Andrew P. Vreede
    • , Shanea K. Estes
    • , Olivia R. Palmer
    • , Paula L. Bockenstedt
    • , David J. Pinsky
    • , Joan M. Greve
    • , Jose A. Diaz
    • , Yogendra Kanthi
    •  & Jason S. Knight
  • Article
    | Open Access

    TMCO1 is a recently described endoplasmic reticular Ca2+ channel. Here, the authors show it is important for osteoblast function and bone formation in mice, and identify a novel pathway linking local increases in Ca2+ at the ER surface with the posttranslational modification of RUNX2.

    • Jianwei Li
    • , Caizhi Liu
    • , Yuheng Li
    • , Qiaoxia Zheng
    • , Youjia Xu
    • , Beibei Liu
    • , Weijia Sun
    • , Yuan Li
    • , Shuhui Ji
    • , Mingwei Liu
    • , Jing Zhang
    • , Dingsheng Zhao
    • , Ruikai Du
    • , Zizhong Liu
    • , Guohui Zhong
    • , Cuiwei Sun
    • , Yanqing Wang
    • , Jinping Song
    • , Shu Zhang
    • , Jun Qin
    • , Shukuan Ling
    • , Xianhua Wang
    •  & Yingxian Li
  • Article
    | Open Access

    Excessive mechanical stress promotes the development of osteoarthritis. Here Chang et al. identify gremlin-1 as a factor expressed in chondrocytes in response to mechanical stress, and contributing to osteoarthritis via activation of the NF-κB pathway.

    • Song Ho Chang
    • , Daisuke Mori
    • , Hiroshi Kobayashi
    • , Yoshifumi Mori
    • , Hideki Nakamoto
    • , Keita Okada
    • , Yuki Taniguchi
    • , Shurei Sugita
    • , Fumiko Yano
    • , Ung-il Chung
    • , Joo-ri Kim-Kaneyama
    • , Motoko Yanagita
    • , Aris Economides
    • , Ernesto Canalis
    • , Di Chen
    • , Sakae Tanaka
    •  & Taku Saito
  • Article
    | Open Access

    Parathyroid hormone (PTH) is used to treat osteoporosis, but its therapeutic mechanism remains unclear. Here, the authors show that Tgif1 is a PTH target gene, and that its deletion impairs the function of osteoblasts and PTH-induced bone formation in mice.

    • Hiroaki Saito
    • , Andreas Gasser
    • , Simona Bolamperti
    • , Miki Maeda
    • , Levi Matthies
    • , Katharina Jähn
    • , Courtney L. Long
    • , Hartmut Schlüter
    • , Marcel Kwiatkowski
    • , Vaibhav Saini
    • , Paola Divieti Pajevic
    • , Teresita Bellido
    • , Andre J. van Wijnen
    • , Khalid S. Mohammad
    • , Theresa A. Guise
    • , Hanna Taipaleenmäki
    •  & Eric Hesse
  • Article
    | Open Access

    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
    • , Matthew E. Johnson
    • , Elisabetta Manduchi
    • , Chun Su
    • , Sumei Lu
    • , Michelle E. Leonard
    • , Kenyaita M. Hodge
    • , James A. Pippin
    • , Kurt D. Hankenson
    • , Andrew D. Wells
    •  & Struan F. A. Grant
  • Article
    | Open Access

    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
    • , Rachel S. Graham
    • , Yohan Kim
    • , Jerel Mueller
    • , Jennifer L. Auger
    • , Nathaniel J. Schuldt
    • , Claire R. W. Kaiser
    • , Abigail P. Heiller
    • , Raini Dutta
    • , Hongsun Guo
    • , Jamu K. Alford
    • , Bryce A. Binstadt
    •  & Hubert H. Lim
  • Article
    | Open Access

    Dermal myofibroblasts are responsible for fibrosis development in scleroderma. Here the authors show that a bioengineered recombinant human TRAIL ligand reverses established fibrosis in mouse models of scleroderma by targeting the death receptor 5 and inducing apoptosis of myofibroblasts.

    • Jong-Sung Park
    • , Yumin Oh
    • , Yong Joo Park
    • , Ogyi Park
    • , Hoseong Yang
    • , Stephanie Slania
    • , Laura K. Hummers
    • , Ami A. Shah
    • , Hyoung-Tae An
    • , Jiyeon Jang
    • , Maureen R. Horton
    • , Joseph Shin
    • , Harry C. Dietz
    • , Eric Song
    • , Dong Hee Na
    • , Eun Ji Park
    • , Kwangmeyung Kim
    • , Kang Choon Lee
    • , Viktor V. Roschke
    • , Justin Hanes
    • , Martin G. Pomper
    •  & Seulki Lee
  • Article
    | Open Access

    Mammalian joints have poor regenerative capacity following amputation. Here, the authors show that in mice, stimulation of the amputation wound with BMP2 and BMP9 stimulates regeneration of a synovial joint that includes bone, cartilage and a synovial cavity.

    • Ling Yu
    • , Lindsay A. Dawson
    • , Mingquan Yan
    • , Katherine Zimmel
    • , Yu-Lieh Lin
    • , Connor P. Dolan
    • , Manjong Han
    •  & Ken Muneoka
  • Article
    | Open Access

    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
    • , Jack A Bibby
    • , Wing Wu
    • , Klaus Stensgaard Frederiksen
    • , Ceri A. Roberts
    • , Zoe Hall
    • , Gaelle LeFriec
    • , Kevin A. Robertson
    • , Paul Lavender
    • , Jens Gammeltoft Gerwien
    • , Leonie S. Taams
    • , Julian L. Griffin
    • , Emanuele de Rinaldis
    • , Lisa G. M. van Baarsen
    • , Claudia Kemper
    • , Peter Ghazal
    •  & Andrew P. Cope
  • Article
    | Open Access

    Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.

    • Jun-Ha Hwang
    • , A Rum Kim
    • , Kyung Min Kim
    • , Jung Il Park
    • , Ho Taek Oh
    • , Sung A Moon
    • , Mi Ran Byun
    • , Hana Jeong
    • , Hyo Kyung Kim
    • , Michael B. Yaffe
    • , Eun Sook Hwang
    •  & Jeong-Ho Hong
  • Article
    | Open Access

    Osteoarthritis (OA) is associated with cartilage degeneration, and no effective therapy exists. Here, the authors show that the HPIP protein modulates OA progression by regulating Wnt signaling, and that its knockdown in joints via AAV-mediated gene silencing attentuates pathology.

    • Quanbo Ji
    • , Xiaojie Xu
    • , Lei Kang
    • , Yameng Xu
    • , Jingbo Xiao
    • , Stuart B. Goodman
    • , Xiang Zhu
    • , Wenchao Li
    • , Juan Liu
    • , Xu Gao
    • , Zhifeng Yan
    • , Yuxuan Zheng
    • , Zheng Wang
    • , William J. Maloney
    • , Qinong Ye
    •  & Yan Wang
  • 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
    • , Xiao Lv
    • , Shouan Zhu
    • , Gehua Zhen
    • , Mei Wan
    • , Amit Jain
    • , Bo Gao
    • , Yu Chai
    • , Mi Yang
    • , Xiao Wang
    • , Ruoxian Deng
    • , Lei Wang
    • , Yong Cao
    • , Shuangfei Ni
    • , Shen Liu
    • , Wen Yuan
    • , Huajiang Chen
    • , Xinzhong Dong
    • , Yun Guan
    • , Huilin Yang
    •  & Xu Cao
  • Article
    | Open Access

    Estrogen promotes negative energy balance and preserves skeletal physiology. Here the authors show that loss of estrogen signalling after ablating estrogen receptor alpha (ERa) in specific hypothalamic neuronal populations leads to a marked sex-dependent increase in bone mass in female mice.

    • Candice B. Herber
    • , William C. Krause
    • , Liping Wang
    • , James R. Bayrer
    • , Alfred Li
    • , Matthew Schmitz
    • , Aaron Fields
    • , Breanna Ford
    • , Zhi Zhang
    • , Michelle S. Reid
    • , Daniel K. Nomura
    • , Robert A. Nissenson
    • , Stephanie M. Correa
    •  & Holly A. Ingraham
  • Article
    | Open Access

    Osteoarthritis is characterised by degeneration of joint cartilage. Here the authors show that the RNA-binding protein ZFP36L1 is upregulated in chondrocytes of humans and mice with osteoarthritis, and that its knockdown in mouse joints protects chondrocytes against apoptosis by modulating the function of heat shock proteins.

    • Young-Ok Son
    • , Hyo-Eun Kim
    • , Wan-Su Choi
    • , Churl-Hong Chun
    •  & Jang-Soo Chun
  • 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
    • , Céline Mortier
    • , Mark E. Labadia
    • , Tine Decruy
    • , Julie Coudenys
    • , Kathleen Hoyt
    • , Anita L. Wayne
    • , Robert Hughes
    • , Michael Turner
    • , Sofie Van Gassen
    • , Liesbet Martens
    • , Dustin Smith
    • , Christian Harcken
    • , Joseph Wahle
    • , Chao-Ting Wang
    • , Eveline Verheugen
    • , Nadia Schryvers
    • , Gaëlle Varkas
    • , Heleen Cypers
    • , Ruth Wittoek
    • , Yves Piette
    • , Lieve Gyselbrecht
    • , Serge Van Calenbergh
    • , Filip Van den Bosch
    • , Yvan Saeys
    • , Gerald Nabozny
    •  & Dirk Elewaut
  • Article
    | Open Access

    Optogenetics is a promising alternative approach for restoration of neuromuscular function. Here the authors establish a closed-loop functional optogenetic stimulation for the control of limb joint angle in murine models, which demonstrates improved control and less fatigue than electrical stimulation systems.

    • Shriya S. Srinivasan
    • , Benjamin E. Maimon
    • , Maurizio Diaz
    • , Hyungeun Song
    •  & Hugh M. Herr
  • Article
    | Open Access

    B cells contribute to rheumatoid arthritis pathogenesis and bone erosion, but the underlying mechanisms are still unclear. Here the authors show, using mouse models and patient tissues, that B cells directly inhibit osteoblast differentiation by producing CCL3 and TNF, thereby providing a potentially new direction for arthritis therapy.

    • Wen Sun
    • , Nida Meednu
    • , Alexander Rosenberg
    • , Javier Rangel-Moreno
    • , Victor Wang
    • , Jason Glanzman
    • , Teresa Owen
    • , Xichao Zhou
    • , Hengwei Zhang
    • , Brendan F. Boyce
    • , Jennifer H. Anolik
    •  & Lianping Xing
  • Article
    | Open Access

    Myoblast fusion in skeletal muscle is a complex process but how this is regulated is unclear. Here, the authors identify Ash1L, a histone methyltransferase, as modulating myoblast fusion via activation of the myogenesis gene Cdon, and observe decreased Ash1L expression in Duchenne muscular dystrophy.

    • Ilaria Castiglioni
    • , Roberta Caccia
    • , Jose Manuel Garcia-Manteiga
    • , Giulia Ferri
    • , Giuseppina Caretti
    • , Ivan Molineris
    • , Kenichi Nishioka
    •  & Davide Gabellini