Featured
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| Open AccessLong-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice
Intervertebral disc degeneration is a leading cause of chronic back pain and disability. Here the authors show that long term treatment with senolytic compounds Dasatinib and Quercetin reduces disc senescence burden and ameliorates age-dependent degeneration in mice.
- Emanuel J. Novais
- , Victoria A. Tran
- & Makarand V. Risbud
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Article
| Open AccessNGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling.
- Seungyong Lee
- , Charles Hwang
- & Benjamin Levi
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Article
| Open AccessRSPO3 is important for trabecular bone and fracture risk in mice and humans
Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here, the authors show that RSPO3 exerts an important role for vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
- Karin H. Nilsson
- , Petra Henning
- & Claes Ohlsson
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Article
| Open AccessJoint disease-specificity at the regulatory base-pair level
While many genetic loci have been found to be associated with disease, not many have had their causal variants and mechanisms investigated. Here, the authors experimentally dissect two loci near GDF5 which are associated with two different joint disorders and which map to independent regulatory elements.
- Pushpanathan Muthuirulan
- , Dewei Zhao
- & Terence D. Capellini
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Article
| Open AccessTime trajectories in the transcriptomic response to exercise - a meta-analysis
Regular exercise promotes overall health and prevents non-communicable diseases, but the adaptation mechanisms are unclear. Here, the authors perform a meta-analysis to reveal time-specific patterns of the acute and long-term exercise response in human skeletal muscle, and identify sex- and age-specific changes.
- David Amar
- , Malene E. Lindholm
- & Euan A. Ashley
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Article
| Open AccessDevelopment of selective bispecific Wnt mimetics for bone loss and repair
Antibody-based Wnt agonists are able to phenocopy Wnt signaling in vivo resulting in increased bone density, repair, and strength. Here, the authors show that Wnt agonists can reverse bone loss associated with ovariectomy and build stronger bone when administered after fracture.
- Tristan W. Fowler
- , Troy L. Mitchell
- & Yang Li
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Article
| Open AccessFKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
FKRP mutations cause muscular dystrophies with varied clinical presentations. The target of FKRP is α-dystroglycan, but here the authors show that FKRP also directs sialylation of fibronectin, a process that is essential for recruitment o collagen to the muscle basement membrane.
- A. J. Wood
- , C. H. Lin
- & P. D. Currie
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Article
| Open AccessTRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration
Supplementation of magnesium (Mg2+) or its inclusion in biomaterials has beneficial effects for bone formation, but it has also been reported that it can have detrimental effects. Here, the authors analyse dose- and time-dependent effects of Mg2+ on bone regeneration and show that it can stimulate monocyte-macrophage lineage cells to support bone formation in the early phases of repair, but inhibit bone repair and mineralization in later stages by promoting a pro-inflammatory environment.
- Wei Qiao
- , Karen H. M. Wong
- & Kelvin W. K. Yeung
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Article
| Open AccessOsteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
Osteocytes are the master regulatory cells within the skeleton. Here, the authors map the transcriptome of osteocytes from diverse skeletal sites, ages and between sexes and identify an osteocyte transcriptome signature associated with rare skeletal disorders and common complex skeletal diseases.
- Scott E. Youlten
- , John P. Kemp
- & Peter I. Croucher
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Article
| Open AccessSLPI is a critical mediator that controls PTH-induced bone formation
The mechanism by which parathyroid hormone mediates the switch from bone resorption to bone formation is unclear. Here, the authors show that SLPI regulates the communication between osteoblasts and osteoclasts to promote the anabolic effect of parathyroid hormone.
- Akito Morimoto
- , Junichi Kikuta
- & Masaru Ishii
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Article
| Open AccessSkeletal muscle transcriptome in healthy aging
As human skeletal muscle ages, gene expression programs change and reflect damage accumulation and homeostatic resilience mechanisms. Here, the authors present a detailed framework of the global transcriptome that characterizes skeletal muscle during aging in healthy individuals.
- Robert A. Tumasian III
- , Abhinav Harish
- & Luigi Ferrucci
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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 AccessAntagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging
Sarcopenia is the age-associated functional decline and atrophy of muscle fibers, and it has been proposed that it might be counteracted by inducing myofiber hypertrophy. Here, the authors show that expression levels of the ubiquitin ligase UBR4 are increased with ageing, and that whilst its genetic ablation rescues muscle atrophy, it is also associated with reduced protein quality and impaired force production in Drosophila and mouse models.
- Liam C. Hunt
- , Bronwen Schadeberg
- & Fabio Demontis
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Article
| Open AccessMaintenance of type 2 glycolytic myofibers with age by Mib1-Actn3 axis
Muscle atrophy is associated with ageing, but the underlying molecular mechanisms are not well understood. Here, they authors show that ablation of the E3 ubiquitin ligase Mib1 is important for myofibre maintenance via a mechanism that involves targeting and degradation of Actn3, and that Mib1 ablation in mice induces muscle atrophy which can be rescued by knockown of Actn3 expression.
- Ji-Yun Seo
- , Jong-Seol Kang
- & Young-Yun Kong
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Article
| Open AccessA scalable physician-level deep learning algorithm detects universal trauma on pelvic radiographs
Pelvic radiographs (PXRs) are essential for detecting proximal femur and pelvis injuries in trauma patients, but none of the currently available algorithms can detect all kinds of trauma-related radiographic findings. Here, the authors develop a multiscale deep learning algorithm trained with weakly supervised point annotation.
- Chi-Tung Cheng
- , Yirui Wang
- & Le Lu
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Review Article
| Open AccessPerspectives on skeletal muscle stem cells
Skeletal muscle has a remarkable regenerative capacity, which can largely be attributed to resident muscle stem cells (MuSCs). Here, the authors review the molecular mechanisms regulating MuSC quiescence, activation and proliferation, how these processes are regulated by the stem cell niche, and the role of MuSCs in neuromuscular diseases.
- F. Relaix
- , M. Bencze
- & Taglietti V.
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Article
| Open AccessThe nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization
The nuclear envelope tethers chromatin to the nuclear periphery to control genome architecture. Here, the authors show that Net39 preserves the integrity and gene expression of muscle nuclei in mice, and it may contribute to the pathogenesis of Emery–Dreifuss muscular dystrophy.
- Andres Ramirez-Martinez
- , Yichi Zhang
- & Eric N. Olson
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Article
| Open AccessAccelerating functional gene discovery in osteoarthritis
Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.
- Natalie C. Butterfield
- , Katherine F. Curry
- & J. H. Duncan Bassett
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Review Article
| Open AccessMechanisms of muscle atrophy and hypertrophy: implications in health and disease
Loss of muscle mass is associated with ageing and with a number of diseases such as cancer. Here, the authors review the signaling pathways that modulate protein synthesis and degradation and gain or loss of muscle mass, and discuss therapeutic implications and future directions for the field.
- Roberta Sartori
- , Vanina Romanello
- & Marco Sandri
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Article
| Open AccessDeep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training
Skeletal muscle conveys the beneficial effects of physical exercise but due to its heterogeneity, studying the effects of exercise on muscle fibres is challenging. Here, the authors carry out proteomic analysis of myofibres from freeze-dried muscle biopsies, show fibre-type specific changes in response to exercise, and show that the oxidative and glycolytic muscle fibers adapt differentially to exercise training.
- A. S. Deshmukh
- , D. E. Steenberg
- & J. F. P. Wojtaszewski
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Article
| Open AccessMyonuclear content regulates cell size with similar scaling properties in mice and humans
Muscle fibers are the largest cells in the body and contain less DNA per unit volume than other cells even if they have multiple nuclei. Here, the authors show that the number of nuclei regulates the cell size with similar scaling properties in mice and humans.
- Kenth-Arne Hansson
- , Einar Eftestøl
- & Kristian Gundersen
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Article
| Open AccessNuclear numbers in syncytial muscle fibers promote size but limit the development of larger myonuclear domains
Skeletal muscle is composed of syncytial myofibres, each containing hundreds of nuclei. Through genetic reduction of the number of nuclei per myofibre, the authors confirm that more nuclei produce larger cells but myofibres with fewer nuclei adaptively compensate leading to larger and functional myonuclear domains.
- Alyssa A. W. Cramer
- , Vikram Prasad
- & Douglas P. Millay
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Article
| Open AccessBETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is characterised by progressive muscle degeneration. Here, the authors show that the BET protein BRD4 is increased in the muscle of DMD mouse models, and that pharmacological inhibition of BRD4 leads to reduced muscle pathology in mice, by modulating NADPH oxidase expression.
- Marco Segatto
- , Roberta Szokoll
- & Giuseppina Caretti
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Article
| Open AccessThe neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia
mTORC1 expression is increased during ageing of muscle, and on the other hand, its activation promotes muscle hypertrophy. Here, the authors assess whether mTORC1 has positive or negative effects on ageing, and show that its long-term inhibition preserves muscle mass and function and neuromuscular junction integrity, whereas muscle-specific activation is associated with sarcopenia.
- Daniel J. Ham
- , Anastasiya Börsch
- & Markus A. Rüegg
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Article
| Open AccessPlasticity of muscle synergies through fractionation and merging during development and training of human runners
Motor commands for human locomotion are generated by combination of muscle synergies. In humans, muscle synergies for running exhibit considerable plasticity during child-to-adult development and adult training to meet the constantly changing biomechanical and efficiency demands.
- Vincent C. K. Cheung
- , Ben M. F. Cheung
- & Roy T. H. Cheung
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Article
| Open AccessIdentification of osteogenic progenitor cell-targeted peptides that augment bone formation
Activation of osteogenic cells is essential for bone regeneration. Here, the authors screen a peptide library and identify 2 compounds that promote osteogenic progenitor cell differentiation in vitro, and show that they increase bone formation and fracture repair in mice.
- Min Jiang
- , Ruiwu Liu
- & Wei Yao
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Article
| Open AccessThe unified myofibrillar matrix for force generation in muscle
Skeletal muscle cells have long been considered to be made primarily of many individual, parallel myofibrils. Here, the authors show that the striated muscle contractile machinery forms a highly branched, mesh-like myofibrillar matrix connected across the entire length and width of the muscle cell.
- T. Bradley Willingham
- , Yuho Kim
- & Brian Glancy
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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 AccessDeconstructing sarcomeric structure–function relations in titin-BioID knock-in mice
Titin determines the elasticity of the sarcomere and integrates into both the Z-disc and the M-band. Here, the authors generate a BioID mouse to study the titin interactome at the Z-disc region in neonatal and adult heart and skeletal muscle.
- Franziska Rudolph
- , Claudia Fink
- & Michael Gotthardt
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Article
| Open AccessBone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis
Bone marrow adipose tissue (BMAT) comprises over 10% of total fat mass but its systemic metabolic role is unclear. Here, the authors show that BMAT glucose uptake is not insulin or cold responsive; however, BMAT basal glucose uptake is higher than in white adipose tissue or skeletal muscle, underscoring BMAT’s potential to influence systemic glucose homeostasis.
- Karla J. Suchacki
- , Adriana A. S. Tavares
- & William P. Cawthorn
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Article
| Open AccessTriggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism
Nebulin-based nemaline myopathy is a heterogenous disease with unclear pathological mechanisms. Here, the authors generate a mouse model that mimics the most common genetic cause of the disease and demonstrate that muscle weakness in this model is associated with twisted actin filaments and altered tropomyosin and troponin behaviour.
- Johan Lindqvist
- , Weikang Ma
- & Henk Granzier
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Article
| Open AccessNovel metabolic role for BDNF in pancreatic β-cell insulin secretion
Glucose metabolism is regulated by hypothalamic brain functions and factors produced by peripheral tissues. Here, the authors show that the regulator of food intake Brain-derived neurotrophic factor is also produced and secreted by muscle and stimulates pancreas insulin release.
- Gianluca Fulgenzi
- , Zhenyi Hong
- & Lino Tessarollo
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Article
| Open AccessActive acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation
Denervation of muscle fibres induces muscle atrophy, via mechanisms that remain unclear. Here, the authors show that binding of acetylcoline to its receptor at the neuromuscular junction represses the expression of connexins 43 and 45, which promote atrophy, and is sufficient to prevent denervation-induced loss of myofibre mass.
- Bruno A. Cisterna
- , Aníbal A. Vargas
- & Juan C. Sáez
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Article
| Open AccessEndothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis
An endothelial cell subtype, expressing endomucin and CD31, has been reported to couple angiogenesis with osteogenesis. Here, the authors show that loss of ZEB1 in these cells epigenetically suppresses Notch signaling, leading to impaired angiogenesis and osteogenesis, and that Zeb1 delivery via liposomes ameliorates bone loss in osteoporotic mice
- Rong Fu
- , Wen-Cong Lv
- & Zhao-Qiu Wu
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Article
| Open AccessSestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals
Ageing is associated with muscle atrophy, which negatively impacts quality of life. Here the authors show that expression of sestrins decreases during inactivity and that their overexpression prevents atrophy in mice via modulation of autophagy and protein degradation.
- Jessica Segalés
- , Eusebio Perdiguero
- & Pura Muñoz-Cánoves
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Article
| Open AccessMitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities
Sarcopenia is the loss of muscle mass and strength associated with physical disability during ageing. Here, the authors analyse muscle biopsies from 119 patients with sarcopenia and age-matched controls of different ethnic groups and find transcriptional signatures indicating mitochondrial dysfunction, associated with reduced mitochondria numbers and lower NAD+ levels in older individuals with sarcopenia.
- Eugenia Migliavacca
- , Stacey K. H. Tay
- & Jerome N. Feige
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Article
| Open AccessHuman muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7
Skeletal muscle stem cells express the transcription factor Pax7. Here, the authors isolate, from human muscle, cells that are positive for the endothelial marker CLEC14A and show that despite not expressing pax7, these cells regenerate muscle and contribute to the muscle stem cell niche when transplanted into mice.
- Andreas Marg
- , Helena Escobar
- & Simone Spuler
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Article
| Open AccessComplex I is bypassed during high intensity exercise
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
- & Jens Nielsen
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Article
| Open AccessCytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise
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
- & Thomas E. Jensen
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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 AccessDepletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy
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
- & Imed-Eddine Gallouzi
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Article
| Open AccessmTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4
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
- & Markus A. Rüegg
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Article
| Open AccessBioinspired extracellular vesicles embedded with black phosphorus for molecular recognition-guided biomineralization
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
- & Quan Yuan
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Article
| Open AccessTargeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy
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
- & James G. Tidball
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Article
| Open AccessA 3,2-Hydroxypyridinone-based Decorporation Agent that Removes Uranium from Bones In Vivo
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
- & Shuao Wang
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Article
| Open AccessDRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
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
- & Marco Sandri
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Article
| Open AccessPreclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration
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
- & Nadia Benkirane-Jessel
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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 AccessTG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone
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
- & Eric Hesse