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| Open AccessOsteocyte mitochondria regulate angiogenesis of transcortical vessels
Osteocytes are the key cellular components of cortical bone. Here they show that osteocytes transfer mitochondria to the endothelial cells of transcortical vessels (TCVs), which promotes angiogenesis and increases function of the TCV network.
- Peng Liao
- , Long Chen
- & Junjie Gao
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Article
| Open AccessSecretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice
The mechanism by which central secretin regulates metabolism is unclear. Here, the authors show that ventromedial hypothalamus-derived secretin maintains energy and bone homeostasis by controlling food intake and sympathetic nerve activity.
- Fengwei Zhang
- , Wei Qiao
- & Billy Kwok Chong Chow
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Article
| Open AccessRescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics
Here, Shao et. al attribute the reduction in bone mechano-responsiveness seen in type 2 diabetes to abnormal osteocytic calcium dynamics. They identify reduced SERCA2 pump activity as a mediator of this process and show that rescuing SERCA2 significantly improves bone mechanical adaptation in this context.
- Xi Shao
- , Yulan Tian
- & Da Jing
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Article
| Open AccessFunctional and analytical recapitulation of osteoclast biology on demineralized bone paper
Here, authors report demineralized bone paper-based in vitro osteogenic culture and assay platforms that replicate essential bone tissue complexity, osteoclast processes, and drug responses with high fidelity and predictive power.
- Yongkuk Park
- , Tadatoshi Sato
- & Jungwoo Lee
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| Open AccessComprehensive assessment of physiological responses in women during the ESA dry immersion VIVALDI microgravity simulation
To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.
- Adrien Robin
- , Angelique Van Ombergen
- & Nastassia Navasiolava
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Article
| Open AccessBAP1 promotes osteoclast function by metabolic reprogramming
Here, the authors demonstrate that BRCA1-associated protein 1 (Bap1) regulates osteoclast’s capacity to degrade bone. Reprogramming of epigenetic-metabolic axis upon Bap1 loss inhibits bone degradation, preserving bone mass, making it a potential therapeutic target for osteoporosis.
- Nidhi Rohatgi
- , Wei Zou
- & Steven L. Teitelbaum
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Article
| Open AccessBone marrow adiposity modulation after long duration spaceflight in astronauts
Bone marrow adiposity is linked to disease, and it is unknown how it is modulated during space travel. Here, the authors show that astronauts returning from ISS missions had decreased marrow fat and increased hematopoiesis and bone formation, suggesting that adipose reserves in the bone marrow might be used as an energy source to counteract anemia and bone loss associated with space flight.
- Tammy Liu
- , Gerd Melkus
- & Guy Trudel
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Article
| Open AccessMultiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton
Technical challenges have previously hindered the detailed study of in vivo senescent cells. Here, the authors deeply characterize senescent skeletal cells across murine aging, establishing CD24 as a marker of osteolineage cells cleared by senolytics.
- Madison L. Doolittle
- , Dominik Saul
- & Sundeep Khosla
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Article
| Open AccessThe structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase
Hypophosphatasia (HPP) is a bone disease caused by mutations in tissue non-specific alkaline phosphatase (TNAP). Here, authors solved the crystal and cryoEM structures of TNAP, shedding light on the molecular mechanisms underlying HPP.
- Yating Yu
- , Kewei Rong
- & An Qin
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Article
| Open AccessEarly presence of Homo sapiens in Southeast Asia by 86–68 kyr at Tam Pà Ling, Northern Laos
Here the authors report new human fossils from Tam Pà Ling cave, Laos, consisting of a cranial and a tibial fragment, dated to 68–86 thousand years ago. This find confirms that Homo sapiens were present in Southeast Asia by this time and the shape of the fossils indicates they may have descended from non-local populations.
- Sarah E. Freidline
- , Kira E. Westaway
- & Fabrice Demeter
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Article
| Open AccessNeutrophil-derived catecholamines mediate negative stress effects on bone
Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.
- Miriam E. A. Tschaffon-Müller
- , Elena Kempter
- & Stefan O. Reber
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Article
| Open AccessKIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration
The levels of a factor secreted by bone marrow stromal cells, KIAA1199, associate with osteoporotic fracture risk. Here, the authors show that KIAA1199 deficiency can lead to enhanced bone formation, accelerated bone healing, and protects from ovariectomy-induced bone loss.
- Li Chen
- , Kaikai Shi
- & Moustapha Kassem
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Article
| Open AccessIntra-pituitary follicle-stimulating hormone signaling regulates hepatic lipid metabolism in mice
Gonadotropes in the pituitary secrete follicle-stimulating hormone and luteinizing hormone to control gonadal function and fertility, but whether they exert actions on extra-gonadal organs is not fully understood. Here the authors report that gonadotropes regulate liver steatosis independent of the ovaries in mice.
- Sen Qiao
- , Samer Alasmi
- & Ulrich Boehm
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Article
| Open AccessSugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.
- Pei Ying Ng
- , Amy B. P. Ribet
- & Nathan J. Pavlos
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Article
| Open AccessCell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis
Bone maintenance in health and disease depends on bone-resorbing osteoclasts. Whitlock et al. demonstrate that an RNA chaperon -La protein- lives a second life as a key regulator of osteoclast size and function, suggesting a new therapeutic target.
- Jarred M. Whitlock
- , Evgenia Leikina
- & Leonid V. Chernomordik
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Article
| Open AccessAltered sulfation status of FAM20C-dependent chondroitin sulfate is associated with osteosclerotic bone dysplasia
Raine syndrome is associated with loss-of-function mutations of FAM20C. Here we show that Raine-originated mutations abrogate the interaction between FAM20C and C4ST-1 to alter chondroitin sulfate sulfation status and impact biomineralization in vitro and bone mineral density in vivo in mouse models, thereby serving clues for Raine syndrome etiology.
- Toshiyasu Koike
- , Tadahisa Mikami
- & Hiroshi Kitagawa
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Article
| Open AccessModulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open AccessOsteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis
Here, the authors identify interleukin-11 as a mediator of bone-adipose crosstalk during mechanical loading of the bone. Interleukin-11 secreted by the bone acts as a hormone to regulate fat metabolism, in addition to having an autocrine-paracrine effect on bone itself.
- Bingzi Dong
- , Masahiro Hiasa
- & Toshio Matsumoto
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Article
| Open AccessSexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration
How bone-related sexually dimorphic traits are regulated hasn’t been examined at the stem cell level. Here the authors show that skeletal stem cells (SSC), in female but not male mice, are directly controlled by estrogen signaling, which could be augmented to improve fracture repair.
- Tom W. Andrew
- , Lauren S. Koepke
- & Charles K. F. Chan
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Article
| Open AccessTargeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
Antibodies targeting sclerostin can ameliorate postmenopausal osteoporosis but present some cardiovascular risk. Here the authors show that the cardiovascular and skeletal effects of sclerostin are mediated by different loops, suggesting ways to preserve the positive effects on bone formation while avoiding the negative cardiovascular consequences.
- Yuanyuan Yu
- , Luyao Wang
- & Ge Zhang
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Article
| Open AccessPeriosteal stem cells control growth plate stem cells during postnatal skeletal growth
Intramembranous and endochondral bone formation have been considered to be independent processes mediated by independent stem cells. Here the authors show that periosteal stem cells participate in both types of bone formation, supporting endochondral formation by producing Ihh.
- Masayuki Tsukasaki
- , Noriko Komatsu
- & Hiroshi Takayanagi
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Article
| Open AccessOsteocyte CIITA aggravates osteolytic bone lesions in myeloma
Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.
- Huan Liu
- , Jin He
- & Jing Yang
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Article
| Open AccessRunx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells
The transcription factors, Runx1 and Runx2 are critical embryonically for generation of HSCs and osteoblasts, respectively. Here the authors show that adult mice lacking Runx1 and Runx2 in HSC-supporting CAR cells displayed an increase in fibrosis with reduced HSCs in bone marrow.
- Yoshiki Omatsu
- , Shota Aiba
- & Takashi Nagasawa
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Article
| Open AccessSmall extracellular vesicle-mediated miR-320e transmission promotes osteogenesis in OPLL by targeting TAK1
The pathological mechanisms that lead to Ossification of the posterior longitudinal ligament (OPLL) are unclear. Here, the authors show that OPLL ligament cells produce small extracellular vesicles that induce ossification via miR-320e/TAK1 signaling in mice and human posterior longitudinal ligament cells.
- Chen Xu
- , Zicheng Zhang
- & Wen Yuan
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| Open AccessAged bone matrix-derived extracellular vesicles as a messenger for calcification paradox
This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.
- Zhen-Xing Wang
- , Zhong-Wei Luo
- & Hui Xie
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Article
| Open AccessOsteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo
Bone remodeling involves a switch between bone formation and resorption, but the mechanisms is unclear. Here, the authors show that intercellular communication via extracellular vesicles secreted by mature osteoblasts is a key factor for the switching, via a microRNA-mediated mechanism.
- Maki Uenaka
- , Erika Yamashita
- & Masaru Ishii
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Article
| Open AccessAn optogenetic approach for regulating human parathyroid hormone secretion
Parathyroid hormone (PTH) plays a role in maintaining calcium and phosphorus homeostasis, and in secondary hyperparathyroidism excess PTH secretion contributes to bone loss. Here the authors report an optogenetic approach to inhibit PTH secretion in human hyperplastic parathyroid cells, and prevented hyperplastic parathyroid tissue-induced bone loss in mice.
- Yunhui Liu
- , Lu Zhang
- & Fan Yang
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Article
| Open AccessRare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.
- Gyda Bjornsdottir
- , Lilja Stefansdottir
- & Kari Stefansson
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Article
| Open AccessMesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing
Developmental and regenerative bone formation require the removal of chondrocytes and matrix. Here the authors show that these processes involve mesenchymal stromal cell-derived septoclasts, which disappear after the completion of development but re-emerge during fracture healing.
- Kishor K. Sivaraj
- , Paul-Georg Majev
- & Ralf H. Adams
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Article
| Open AccessDivalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models
Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.
- Wei Qiao
- , Dayu Pan
- & Xu Cao
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Article
| Open AccessCholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis
The sympathetic nervous system has been shown to respond to stress and activate haematopoietic stem cells. Here they show that cholinergic signals in the bone marrow preserve haematopoietic stem cell quiescence and self-renewal under proliferative stress.
- Claire Fielding
- , Andrés García-García
- & Simón Méndez-Ferrer
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Article
| Open AccessMacrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis
Visceral adipose tissue secretes cytokines to regulate the homeostasis of organs. Here, the authors show that epididymal white adipose tissue-secreted osteopontin induces lipophagocytic mobilization of macrophages and promotes bone matrix degradation via activating osteoclasts.
- Bingyang Dai
- , Jiankun Xu
- & Ling Qin
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Article
| Open AccessMechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation
Mechanical force is critical for the development and remodeling of bones. Here the authors report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine via regulating the expression of the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 in osteoblasts.
- Ziang Xie
- , Lei Hou
- & Shunwu Fan
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Article
| Open AccessTargeting chondrocytes for arresting bony fusion in ankylosing spondylitis
Current treatments cannot significantly alleviate the radiographic progression in ankylosing spondylitis (AS), which results in joints stiffness and bony fusion of AS. Smo inhibitor sonidegib retards the pathological new bone formation in AS through targeting dysfunctional chondrogenesis.
- Fenli Shao
- , Qianqian Liu
- & Yang Sun
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Article
| Open AccessEngineered osteoclasts as living treatment materials for heterotopic ossification therapy
Heterotopic ossification (HO) is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these calcified plaques. Here, the authors demonstrate that chemically engineered osteoclasts coated with tetracycline can improve their targeting capacity to ectopic calcifications, which extends their bone resorption functions for the treatment of HO.
- Wenjing Jin
- , Xianfeng Lin
- & Ruikang Tang
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| Open AccessQuantitative 3D imaging of the cranial microvascular environment at single-cell resolution
Vascularization is critical for cranial bone growth, maintenance, and healing, but it remains unknown how blood vessels are spatially distributed in the calvarium, and how they interact with skeletal progenitors during these processes. Here, the authors apply a quantitative light-sheet imaging platform to visualize and analyze the relationship between blood vessels and skeletal progenitors throughout the murine calvarium.
- Alexandra N. Rindone
- , Xiaonan Liu
- & Warren L. Grayson
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| Open AccessDamaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors
Concomitant traumatic brain injury accelerates bone healing, but the mechanism is unclear. Here, the authors show that injured neurons, mainly those in the hippocampus, release osteogenic miRNA-enriched small extracellular vesicles, which targete osteoprogenitors to stimulate bone formation.
- Wei Xia
- , Jing Xie
- & Xiaochun Bai
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Article
| Open AccessAutomated bone mineral density prediction and fracture risk assessment using plain radiographs via deep learning
Dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool are recommended tools for osteoporotic fracture risk evaluation, but are underutilized. Here, the authors present an opportunistic tool to identify fractures, predict bone mineral density and evaluate fracture risk using plain pelvis and lumbar spine radiographs.
- Chen-I Hsieh
- , Kang Zheng
- & Chang-Fu Kuo
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Article
| Open AccessTNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis
Abnormal functions of mesenchymal stem cells (MSC) contribute into the pathogenensis of ankylosing spondylitis (AS). Here, the authors show that TNF-α at high concentration induces enhances migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3′ UTR.
- Zhongyu Xie
- , Wenhui Yu
- & Huiyong Shen
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Article
| Open AccessELMO1 signaling is a promoter of osteoclast function and bone loss
Osteoporosis and bone fractures affect millions of patients worldwide and are often due to increased bone resorption. Here the authors identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ promoting the bone resorption function of osteoclasts.
- Sanja Arandjelovic
- , Justin S. A. Perry
- & Kodi S. Ravichandran
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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 AccessTargeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.
- Dali Zhang
- , Junlan Huang
- & Yangli Xie
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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 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 AccessDirect contribution of skeletal muscle mesenchymal progenitors to bone repair
Bone regeneration involves activation of tissue resident stem cells. Here the authors show that mesenchymal progenitors from skeletal muscle mediate the fibrotic response to bone injury and also contribute to bone repair; processes that are impaired when both muscle and bone are injured.
- Anais Julien
- , Anuya Kanagalingam
- & Céline Colnot
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Article
| Open AccessSelenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts
Selenoproteins containing selenium have a variety of physiological functions including redox homeostasis and thyroid hormone metabolism. Here, the authors show that RANKL-dependent repression of selenoprotein W regulates cell fusion during osteoclast differentiation and bone remodelling in mice.
- Hyunsoo Kim
- , Kyunghee Lee
- & Daewon Jeong
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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 AccessOsteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis
Glucocorticoids (GCs) inhibit bone angiogenesis and affect bone development, but the underlying mechanisms remain unclear. Here, the authors show that GCs induce vascular cell senescence during bone development by inhibiting angiogenin secretion from osteoclasts, impairing angiogenesis via endothelial Plexin B2, resulting in unpaired bone growth.
- Xiaonan Liu
- , Yu Chai
- & Mei Wan