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| Open AccessSuppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1
Authors explore the biological mechanisms underlying a missing digit joint in Brachydactyly type A1. They showed that excess Indian Hedgehog proteins suppress the apoptosis level needed for the progression of digit joint development in a mouse model.
- Adrian On Wah Leung
- , Andrew Chung Hin Poon
- & Danny Chan
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Article
| Open AccessSpecific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia
Biallelic loss-of-function variants in the gene encoding Matrix Gla Protein (MGP) are known to cause a recessive disorder called Keutel syndrome. Here, the authors report that heterozygous missense variants affecting one particular cysteine residue of MGP can cause a clinically distinct, dominant disorder, likely via impaired signal peptide processing leading to cellular stress and apoptosis.
- Ophélie Gourgas
- , Gabrielle Lemire
- & Monzur Murshed
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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 AccessSingle-cell analysis of lizard blastema fibroblasts reveals phagocyte-dependent activation of Hedgehog-responsive chondrogenesis
Lizards are the closest known relatives of mammals capable of epimorphic tail regrowth. Here, single-cell analysis of regenerating lizard tails reveals a phagocyte-induced fibroblast population contributing to blastema formation and chondrogenesis.
- Ariel C. Vonk
- , Xiaofan Zhao
- & Thomas P. Lozito
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| Open AccessThe NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice
Deficiency in NAD+ has been implicated in skeletal deformities during development in both humans and mice. Here, the authors use mice that lack the critical enzyme of the NAD+ salvage pathway Nampt in mesenchymal lineage cells to show that the NAD salvage pathway is indispensable for endochondral but not intramembranous bone development.
- Aaron Warren
- , Ryan M. Porter
- & Maria Almeida
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| Open AccessDirectionality of developing skeletal muscles is set by mechanical forces
The mechanisms that drive myocyte orientation and fusion to control muscle directionality are not well understood. Here authors show that the developing skeleton produces mechanical tension that instructs the directional outgrowth of skeletal muscles.
- Kazunori Sunadome
- , Alek G. Erickson
- & Igor Adameyko
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Article
| Open AccessPaternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
Anti-folate drugs, such as methotrexate, have been largely prohibited for pregnant women because of the teratogenic effect on their descendant. Here, the authors report a intergenerational mechanism by why paternal methotrexate exposure causes craniofacial defects on their offspring.
- Nagif Alata Jimenez
- , Mauricio Castellano
- & Pablo H. Strobl-Mazzulla
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| Open AccessThe fate of early perichondrial cells in developing bones
In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. Here they show that perichondrial cells are destined to become adipocyte-biased stromal cells, indicating that marrow stromal compartments are defined by their cells of origin.
- Yuki Matsushita
- , Angel Ka Yan Chu
- & Noriaki Ono
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Article
| Open AccessCreb5 coordinates synovial joint formation with the genesis of articular cartilage
Zhang et al. show that the Creb5 transcription factor regulates the formation of synovial joints, directs the genesis of articular cartilage, and regulates the shape of the ends of long bones by blocking Wnt5a expression in the perichondrium.
- Cheng-Hai Zhang
- , Yao Gao
- & Andrew B. Lassar
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| Open AccessAltered developmental programs and oriented cell divisions lead to bulky bones during salamander limb regeneration
Normal limb development relies on synchronized formation of cartilage and bone. Here, the authors show that in salamander limb regeneration these processes are decoupled: ossification occurs after the final size of regenerating cartilage is reached, allowing fast regeneration and leading to bulky bones.
- Marketa Kaucka
- , Alberto Joven Araus
- & Igor Adameyko
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Article
| Open AccessWRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome
Short stature is a hallmark of Werner Syndrome, but the underlying mechanisms are not well studied. Here they report that WRN regulates bone development and growth by opening SHOX-G-quadruplexes via its helicase activity both in vitro and in vivo.
- Yuyao Tian
- , Wuming Wang
- & Wai-Yee Chan
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Article
| Open AccessMast4 determines the cell fate of MSCs for bone and cartilage development
Controlling fate decision of mesenchymal stromal cells (MSC) is important for their clinical application. Here the authors demonstrate that TGF-β-induced Mast4 suppression and Wnt-mediated Mast4 stabilization regulate MSC differentiation into cartilage and bone, respectively.
- Pyunggang Kim
- , Jinah Park
- & Seong-Jin Kim
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Article
| Open AccessA FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury
The growth plate cartilage supports long bone growth. Here the authors identify FoxA2+ long term stem cells in the growth plate that are stratified with short term PTHrP+ cells, participate in production of hyaline cartilage, expand in response to trauma, and whose ablation impairs cartilage regeneration.
- Shanmugam Muruganandan
- , Rachel Pierce
- & Andreia M. Ionescu
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| Open AccessTranscriptional profiling of mESC-derived tendon and fibrocartilage cell fate switch
The transcriptional regulators underlying the induction and differentiation of dense connective tissues remain largely unknown. Here the authors generate tendon and fibrocartilage cells from mouse embryonic stem cells and apply scRNA-seq to identify molecular regulation of the cell fate switch between these lineages.
- Deepak A. Kaji
- , Angela M. Montero
- & Alice H. Huang
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| 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 AccessHox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life
Prior evidence suggested mesenchymal stromal cells (MSCs) required for skeletal formation, maintenance, and repair arise postnatally. Here, the authors show that Hoxa11 lineage-marked cells give rise to all skeletal lineages from embryogenesis through adulthood and are upstream progenitors of LepR- and Osx-lineage MSCs
- Kyriel M. Pineault
- , Jane Y. Song
- & Deneen M. Wellik
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Article
| Open AccessBMP9 stimulates joint regeneration at digit amputation wounds in mice
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
- & Ken Muneoka
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Article
| Open AccessGlucose metabolism induced by Bmp signaling is essential for murine skeletal development
It is unclear how metabolic regulation affects development of the skeleton. Here, the authors show that deletion of the glucose transporter Glut1 (Slc2a1) both prior to and following chondrogenesis in the mouse limb impairs chondrocyte proliferation and shortening of the limbs, modulated by BMP signaling.
- Seung-Yon Lee
- , E. Dale Abel
- & Fanxin Long
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| Open AccessReciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation
Inflammation can promote cartilage degradation by inducing matrix-degrading enzymes via NF-κB. Here the authors uncover reciprocal inhibition of Yap/Taz and NF-κB signaling though TAK1, and identify Yap activity as critical for maintenance of cartilage integrity in a mouse model of osteoarthritis.
- Yujie Deng
- , Jinqiu Lu
- & Kinglun Kingston Mak
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| Open AccessMapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes
Human development provides a roadmap for advancing pluripotent stem cell-based regenerative therapies. Here the authors mapped human skeletogenesis using RNA sequencing on 5 cell types from a single foetal stage as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation.
- Gabriel B. Ferguson
- , Ben Van Handel
- & Denis Evseenko
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| Open AccessDesumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway
Osteochondroprogenitors are essential cells for skeletal development and homeostasis. Here the authors show that the desumoylase SENP6 suppresses p53 activity by desumoylating and stabilising TRIM28, and that SENP6 ablation leads to skeletal abnormalities, senescence in osteochondroprogenitors and chondrocytes, and premature ageing.
- Jianshuang Li
- , Di Lu
- & Tao Yang
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| Open AccessEZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy
EZH1 and EZH2 are associated with epigenetic bone and cartilage developmental defects. Here the authors show that cartilage-specific double knockout mice have reduced skeletal growth and how these histone methyltransferases regulate chondrogenesis and endochondral bone development.
- Julian C. Lui
- , Presley Garrison
- & Jeffrey Baron
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Article
| 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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Article
| Open AccessKindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis
The Kidlins are proteins found in cell focal adhesion sites where they regulate integrins, and in the nucleus where their role is unknown. Here the authors show that Kindlin-2 controls chondrogenesis by regulating integrin b1 activation and Sox9 and TGF-β nuclear signalling.
- Chuanyue Wu
- , Hongli Jiao
- & Guozhi Xiao
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Article
| Open AccessA genome-wide association study identifies multiple loci for variation in human ear morphology
The shape of the pinna varies widely in the general human population but the genetic basis of this variation is unknown. Here Adhikari et al. conduct a genome-wide association study in Latin Americans and discover seven gene regions influencing pinna morphology, including EDAR and TBX15.
- Kaustubh Adhikari
- , Guillermo Reales
- & Andrés Ruiz-Linares
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| Open AccessDynamic imaging of the growth plate cartilage reveals multiple contributors to skeletal morphogenesis
It is largely unknown how individual cell behaviours translate into collective cell action that underlies bone morphogenesis. Here the authors perform quantitative imaging of the long bone cartilage growth plate and identify the key cellular mechanisms of cartilage morphogenesis.
- Yuwei Li
- , Vikas Trivedi
- & Scott E. Fraser
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Article |
Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25
Sox9 is an important transcription factor in the formation of cartilage chondrogenesis that occurs during skeletal development. Nakamuraet al.show that Sox9 interacts with Wwp2 and Med25 to form a complex and that loss of either protein in zebrafish results in altered palate chondrogenesis.
- Yukio Nakamura
- , Koji Yamamoto
- & Haruhiko Akiyama