Featured
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| Open AccessA landscape of gene expression regulation for synovium in arthritis
Hundreds of arthritis-associated genetic variants have been identified but in most cases their functions remain unknown. Here the authors develop a resource to reveal the effects of variants on gene expression in human synovium, and identify arthritis-related genes.
- Feng Jiang
- , Shou-Ye Hu
- & Tie-Lin Yang
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Article
| Open AccessMechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks
The 24-hour circadian clocks in cartilage and intervertebral disc play key roles in regulating tissue physiology, yet how they are reset on a daily basis remains elusive. Here the authors show that daily patterns of mechanical loading and associated changes in osmolarity provide a tissue-type specific entrainment time cue for these skeletal clocks.
- Michal Dudek
- , Dharshika R. J. Pathiranage
- & Qing-Jun Meng
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| Open AccessLoss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis
This study reveals an important chondrocytic progenitor population for maintenance of adult articular cartilage marked by Gremlin 1. Loss of these progenitors causes osteoarthritis and suggests methods to sustain them may be effective future targets for management of osteoarthritis.
- Jia Q. Ng
- , Toghrul H. Jafarov
- & Siddhartha Mukherjee
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| Open AccessBone disease imaging through the near-infrared-II window
Skeletal disorders are commonly diagnosed by X-ray imaging, but the radiation limits its use. Here, the authors show that intravital NIR-II bone imaging is effective in diagnosis of a series of common bone diseases non-invasively in mice.
- Chao Mi
- , Xun Zhang
- & Dayong Jin
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| Open AccessMYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling
Age is the greatest risk factor for osteoarthritis (OA) and chondrocyte senescence is an important cellular event that contributes to OA development. This study shows that clathrin-mediated endocytosis and activation of Notch signaling promotes articular chondrocyte senescence and OA development, which is negatively regulated by myosin light chain 3 (MYL3).
- He Cao
- , Panpan Yang
- & Kai Li
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| Open AccessPiezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis
Osteoarthritis is characterized by mechanically driven pain but lacks adequate treatments. Here, the authors show that inhibiting a mechanically-sensitive ion channel expressed by nociceptors reduces pain behaviors in mouse models of joint pain.
- Alia M. Obeidat
- , Matthew J. Wood
- & Rachel E. Miller
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Article
| Open AccessEngraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect
Allogeneic iPSC-derived cartilage organoids survive and integrate with surrounding native cartilage without immune reactions in a primate model of chondral defects in the knee joints, being remodeled and functioning as articular cartilage.
- Kengo Abe
- , Akihiro Yamashita
- & Noriyuki Tsumaki
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| Open AccessCholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4
This study demonstrates a role of cholesterol metabolism-related gene, Lrp3, in cartilage degeneration and osteoarthritis pathogenesis. LRP3 positively regulates cartilage extracellular matrix metabolism by targeting syndecan-4 via Ras signalling, implicating the cholesterol-LRP3-SDC4 axis in osteoarthritic cartilage degeneration.
- Chenxi Cao
- , Yuanyuan Shi
- & Yingfang Ao
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Article
| Open AccessRunx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development
Possible distinct contributions of Runx 2 and Runx3 in osteoarthritis have not been clarified. Nagata et al. show that Runx3 protects adult articular cartilage by extracellular matrix protein production in normal conditions, while Runx2 exerts both catabolic and anabolic effects during inflammation.
- Kosei Nagata
- , Hironori Hojo
- & Taku Saito
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Article
| Open AccessDual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.
- Yun Zhang
- , Shuaijun Li
- & Lei Cui
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Article
| Open AccessSelenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis
Osteoarthritis is caused by the gradual accumulation of oxidative stress in cartilage. Here, the authors show that dysregulation of the selenium metabolic pathway underlies a shift in redox homeostasis in chondrocytes, leading to chronic osteoarthritic changes in joints.
- Donghyun Kang
- , Jeeyeon Lee
- & Jin-Hong Kim
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Article
| Open AccessPPARα−ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis
Increasing evidence suggested that dysregulation in lipid metabolism is linked to OA pathogenesis, but the underlying regulatory mechanism is not well understood. Here, the authors show that PPARα-ACOT12 signalling regulates cartilage homeostasis by regulating de novo lipogenesis in mice.
- Sujeong Park
- , In-Jeoung Baek
- & Eun-Jung Jin
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Article
| Open AccessBoth microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis
Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
- Yoshiaki Ito
- , Tokio Matsuzaki
- & Hiroshi Asahara
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Article
| Open 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 AccessOsteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins
The innate immune system and inflammation modulate bone homeostasis through complex regulation of bone remodelling cells including osteoblasts and osteoclasts. Here, the authors show that the type I interferon pathway and guanylate binding proteins functionally limit bone loss by inhibiting osteoclast functions.
- David E. Place
- , R. K. Subbarao Malireddi
- & Thirumala-Devi Kanneganti
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Article
| Open AccessSingle cell transcriptomic analysis of human pluripotent stem cell chondrogenesis
Application of human induced pluripotent stem cells (hiPSCs) for tissue regeneration is hindered by off-target cell differentiation. Here, the authors use bulk and single cell RNA-sequencing to identify WNT and MITF as off-target hubs during chondrogenic differentiation; inhibiting these pathways enhanced homogeneity and yield.
- Chia-Lung Wu
- , Amanda Dicks
- & Farshid Guilak
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Article
| Open AccessOsteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation
Osteoarthritis (OA) is associated with cartilage disruption, but the underlying mechanisms remain unclear. Here, the authors show that expression of osteoclast-associated receptor (OSCAR) is associated with OA, that its genetic ablation or targeting with OSCAR-Fc fusion protein ameliorates OA in mice by decreasing chondrocyte apoptosis.
- Doo Ri Park
- , Jihee Kim
- & Soo Young Lee
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| 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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| Open AccessEnvironmental arginine controls multinuclear giant cell metabolism and formation
Multinucleated giant cells (MGCs) are important in the pathogenesis of various diseases. Here, the authors demonstrate that extracellular presence of the amino acid arginine is required for MGC formation and metabolism, suggesting a translational impact for strategies utilizing systemic arginine depletion in MGC-mediated diseases.
- Julia S. Brunner
- , Loan Vulliard
- & Gernot Schabbauer
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| Open AccessTankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation
Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.
- Sukyeong Kim
- , Sangbin Han
- & Jin-Hong Kim
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Article
| Open AccessIntestinal microbiome composition and its relation to joint pain and inflammation
Alterations to the microbiome are now associated with various diseases. Here the authors analyze microbiomes from a large population based cohort and show positive correlations between abundance of Streptococcus spp. and osteoarthritis-related knee pain.
- Cindy G. Boer
- , Djawad Radjabzadeh
- & Joyce B. J. van Meurs
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Article
| Open AccessThe microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression
Osteoarthritis involves whole-joint tissue degeneration. Here, the authors show that miR-204 and miR-211 in mesenchymal joint cells regulate their proliferation, catabolic and osteogenic responses, and that disease progression is ameliorated by intra-articular miR-204 delivery in mice.
- Jian Huang
- , Lan Zhao
- & Di Chen
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Article
| Open AccessFunctional testing of thousands of osteoarthritis-associated variants for regulatory activity
GWAS have identified risk loci for osteoarthritis (OA), but the causal variants still have to be determined. Here, the authors apply a massively-parallel reporter assay to screen 1,605 candidate SNPs in 35 OA loci, which prioritizes six SNPs in four loci, one of which, rs4730222, is characterized in more detail.
- Jason C. Klein
- , Aidan Keith
- & Jay Shendure
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Article
| Open AccessWwp2 maintains cartilage homeostasis through regulation of Adamts5
Wwp2 is an HECT-type E3 ubiquitin ligase abundantly expressed in articular cartilage. Here, the authors show that in mice, loss of Wwp2 leads to upregulated Runx2-Adamts5 signaling in articular cartilage and development of osteoarthritis, and that disease severity is reduced by injection of Wwp2 mRNA
- Sho Mokuda
- , Ryo Nakamichi
- & Hiroshi Asahara
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Article
| Open AccessGWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures
Size and shape of bones are important for height and body shape. Here, Styrkarsdottir et al identify 12 loci in a GWAS for bone area derived from DXA scans and show that these loci associate with other bone-related phenotypes including osteoarthritis, height, bone mineral density and risk of hip fracture.
- Unnur Styrkarsdottir
- , Olafur A. Stefansson
- & Kari Stefansson
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Article
| Open 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 AccessExcessive mechanical loading promotes osteoarthritis through the gremlin-1–NF-κB pathway
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
- & Taku Saito
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Article
| Open AccessHematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis
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
- & Yan Wang
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| Open AccessRNA-binding protein ZFP36L1 regulates osteoarthritis by modulating members of the heat shock protein 70 family
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
- & Jang-Soo Chun
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| Open AccessDysregulation of the NUDT7-PGAM1 axis is responsible for chondrocyte death during osteoarthritis pathogenesis
Osteoarthritis is a common joint disease that is a major public health problem. Here, the authors identify a role for the NUDT7 protein in pathogenesis of the disease, and report the potential for NUDT7 to be a target for future therapies.
- Jinsoo Song
- , In-Jeoung Baek
- & Eun-Jung Jin
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| Open AccessEstrogen-related receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes
The pathogenesis of osteoarthritis is unclear. The authors show that estrogen-related receptor gamma is upregulated in cartilage from patients and mouse models, where it drives production of matrix-degrading MMPs in chondrocytes, and that its downregulation ameliorates pathology in mice.
- Young-Ok Son
- , Seulki Park
- & Jang-Soo Chun
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| 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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| 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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| Open AccessBiphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes
Rela is a transcription factor shown to have seemingly contradictory roles in anabolism and catabolism of cartilage. Here the authors find that Rela prevents chondrocyte apoptosis and that homozygous knockout causes accelerated osteoarthritis in adults, whereas heterozygous knockout suppresses osteoarthritis by maintaining wild-type effects on apoptosis but inhibiting catabolic gene expression.
- Hiroshi Kobayashi
- , Song Ho Chang
- & Taku Saito
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| 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