• aging
• chronic inflammation
• glucocorticoid
• osteoporosis
• rheumatoid arthritis (RA)

• Breast cancer
• Denosumab
• Immunotherapy
• Mammary gland
• RANK
• RANKL

• Humans
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• RANK Ligand/metabolism
• RANK Ligand/genetics
• RANK Ligand/antagonists & inhibitors
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Receptor Activator of Nuclear Factor-kappa B/genetics
• Signal Transduction/drug effects
• Female
• Animals
• Tumor Microenvironment
• Denosumab/therapeutic use

• Osteoclasts/metabolism
• Cell Differentiation
• Trans-Activators/metabolism
• Trans-Activators/genetics
• Humans
• Female
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Breast Neoplasms/genetics
• Connective Tissue Growth Factor/metabolism
• Animals
• Paracrine Communication
• Mice
• RANK Ligand/metabolism
• Cell Line, Tumor
• Macrophages/metabolism
• Bone Neoplasms/metabolism
• Bone Neoplasms/secondary
• Bone Neoplasms/pathology

• R01 CA271095 NCI NIH HHS
• T32 EB001026 NIBIB NIH HHS
• TL1 TR001858 NCATS NIH HHS
• R21 EY032632 NEI NIH HHS
• R01 CA248873 NCI NIH HHS
• T32 HL129964 NHLBI NIH HHS
• K99 CA267180 NCI NIH HHS

• Autoimmune response
• CNS
• Inflammation
• Microglia
• OPG/RANKL/RANK
• Osteoimmunology

• Humans
• Osteoprotegerin/metabolism
• RANK Ligand/metabolism
• Animals
• Receptor Activator of Nuclear Factor-kappa B/metabolism
• Nervous System Diseases/metabolism
• Signal Transduction/physiology

• GSDME
• Ligustrazine
• caspase-3
• coronary artery calcification
• vascular smooth muscle cells

• Animals
• Pyroptosis/drug effects
• Mice
• Pyrazines/pharmacology
• Pyrazines/therapeutic use
• Caspase 3/metabolism
• Vascular Calcification/drug therapy
• Vascular Calcification/pathology
• Vascular Calcification/metabolism
• Mice, Knockout
• Coronary Artery Disease/drug therapy
• Coronary Artery Disease/pathology
• Muscle, Smooth, Vascular/drug effects
• Muscle, Smooth, Vascular/cytology
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/pathology
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/metabolism
• Reactive Oxygen Species/metabolism
• Cell Line
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Osteoprotegerin/metabolism
• Disease Progression
• Phosphate-Binding Proteins/metabolism
• Gasdermins

• R01 CA248873 NCI NIH HHS
• R01 CA271095 NCI NIH HHS

• Helicobacter pylori
• antibiotics
• disease activity
• eradication
• inflammatory bowel disease

• OPG
• RANKL
• fiber type switch
• mitochondrial biogenesis
• skeletal muscle

• Animals
• RANK Ligand/metabolism
• Mice
• Muscle, Skeletal/metabolism
• Signal Transduction/drug effects
• Mice, Inbred C57BL
• Osteoprotegerin/metabolism
• Oxidation-Reduction
• Muscle Fibers, Skeletal/metabolism
• Muscle Fibers, Skeletal/drug effects
• Mice, Knockout
• Cell Line
• Organelle Biogenesis
• Cell Respiration/drug effects
• Male
• Mitochondria/metabolism

• 2020/15959-5 São Paulo Research Foundation
• Foundation for the Support of Teaching, Research and Service of the University Hospital of Ribeirao Preto Medical School
• 845/2020 University of São Paulo
• CNPq
• National Council for Scientific and Technological Development
• 2022/06359-0 FAPESP

• ageing
• bone development
• cortical bone
• cortical porosity
• mouse models
• osteocytes
• osteoporosis
• preclinical research

• Animals
• Humans
• Cortical Bone
• Disease Models, Animal
• Rats
• Mice
• Bone Diseases
• Rodentia

• University of Melbourne
• Australian Research Council
• NHMRC
• an EH Flack Fellowship from the Marion
• philanthropic support to St

• biological techniques
• cell biology
• chemical biology
• developmental biology

• Humans
• Osteoclasts/metabolism
• Bone Resorption/metabolism
• Blue Light
• Optogenetics
• Cell Differentiation/genetics
• RANK Ligand/metabolism

• 19K22701 Japan Society for the Promotion of Science
• 21H05254 Japan Society for the Promotion of Science
• 21K05499 Japan Society for the Promotion of Science
• Takeda Science Foundation
• Brain science foundation,Japan

• Cardiovascular risk
• Kidney disease
• Mendelian Randomization
• Pathway analysis
• Prediction
• Proteomics

• Humans
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/complications
• Risk Factors
• Proteomics
• Renal Insufficiency, Chronic/complications
• Renal Insufficiency, Chronic/epidemiology
• Risk Assessment
• Atherosclerosis/complications
• Glomerular Filtration Rate/physiology
• Heart Disease Risk Factors

• R01 HL153161 NHLBI NIH HHS
• U01 DK060963 NIDDK NIH HHS
• UL1 RR024131 NCRR NIH HHS
• U01 DK061022 NIDDK NIH HHS
• R01 DK119199 NIDDK NIH HHS
• UL1 TR000003 NCATS NIH HHS
• UL1 TR000439 NCATS NIH HHS
• UL1 RR029879 NCRR NIH HHS
• U01 DK061028 NIDDK NIH HHS
• UL1 TR000433 NCATS NIH HHS
• U01 DK108809 NIDDK NIH HHS
• UL1 TR002548 NCATS NIH HHS
• U01 DK060984 NIDDK NIH HHS
• U01 DK061021 NIDDK NIH HHS
• U24 DK060990 NIDDK NIH HHS
• U01 DK060980 NIDDK NIH HHS
• R01 HL159081 NHLBI NIH HHS
• U01DK108809 and R01HL159081 NIH HHS
• UL1 TR000424 NCATS NIH HHS
• M01 RR016500 NCRR NIH HHS
• P20 GM109036 NIGMS NIH HHS
• U01 DK060902 NIDDK NIH HHS
• U01 DK060990 NIDDK NIH HHS
• UM1 TR004528 NCATS NIH HHS
• National Institutes of Health
• National Institute of Diabetes
• Perelman School of Medicine
• University of Pennsylvania Clinical
• Translational Science
• Johns Hopkins University
• University of Maryland
• Clinical and Translational Science
• National Center for Advancing Translational Sciences
• Medical Research, Michigan Institute for Clinical and Health Research
• University of Illinois at Chicago
• Clinical and Translational Research
• Department of Internal Medicine
• University of New Mexico School of Medicine
• Winkelman Family
• Department of Health and Human

• BMPRII
• GDF
• Pulmonary arterial hypertension (PAH)
• TGF-β
• activin
• biologics
• ligand trap
• monoclonal antibody
• sotatercept

• Humans
• Pulmonary Arterial Hypertension
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/pathology
• Biological Products/pharmacology
• Biological Products/therapeutic use
• Ligands
• Transforming Growth Factor beta/metabolism

• R01 HL144590 NHLBI NIH HHS
• R42 HL151045 NHLBI NIH HHS

• RANKL
• estrogen
• mast cells
• mice
• osteoclasts
• osteoimmunology
• ovariectomy
• post-menopausal osteoporosis

• LSSH1000.19 Hertha Nathorff Foundation of Ulm University
• 251293561, C01 INST 40/491-1 Collaborative Research Center 1149 "Danger Response, Disturbance Factors and Regenerative Potential After Acute Trauma"

• Bone
• Cell fusion
• Osteoclast
• Osteoclastogenesis
• RANKL
• Resorption

• Bone Resorption/metabolism
• Cell Differentiation
• Cells, Cultured
• Humans
• Macrophage Colony-Stimulating Factor/pharmacology
• Osteoclasts/metabolism
• Peptide Hydrolases/metabolism
• Protons

• 3D printing
• Alveolar stem cell(s)
• Dental implant(s)
• Mesh structure
• Microarc Oxidation
• Pull-out test
• Titanium

• Genetics
• Gut microbiome
• Hypophosphatemic rickets
• Osteoporosis
• Paget's disease of bone

• Biology
• Bone Resorption/pathology
• Bone and Bones/pathology
• Humans
• Osteoprotegerin/metabolism
• RANK Ligand/metabolism
• Receptor Activator of Nuclear Factor-kappa B/metabolism

• R01 AI125284 NIAID NIH HHS
• R01 AR069546 NIAMS NIH HHS
• R01 AR077526 NIAMS NIH HHS
• R01 AR080021 NIAMS NIH HHS

• Bone development
• Hematopoietic stem cell
• Osteoclast
• Yolk sac

The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor‐kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)‐induced hypertension.

Mortality was higher (P<0.0001 by log‐rank test) in 8‐week‐old male homozygotes of osteoprotegerin gene‐knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age‐matched wild‐type mice. Ang II‐infused aorta of wild‐type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor‐kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all‐cause mortality (P<0.001 by log‐rank test), the incidence of fatal aortic rupture (P=0.08), and aortic dissection (P<0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor‐kappa B ligand concentrations in Ang II‐infused osteoprotegerin gene‐knockout mice.

These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II‐induced hypertension by inhibiting receptor activator of nuclear factor‐kappa B ligand activity and periostin expression.

• aortic dissection
• elastin
• extracellular matrix
• proteoglycan

• PTH
• PTHrP
• adenylyl cyclase
• cAMP
• osteoblasts
• osteoclasts
• protein kinase A

• Cyclic AMP/metabolism
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Osteoblasts
• Parathyroid Hormone/metabolism
• Receptor, Parathyroid Hormone, Type 1/metabolism

• Bone formation
• Bone remodelling
• Bone resorption
• Coupling
• Osteoblasts
• Osteoclasts
• Osteoporosis

• Bone Resorption
• Bone and Bones
• Cell Communication
• Humans
• Osteoblasts
• Osteoclasts
• RANK Ligand

Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A’s influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs’ osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration.

• Interleukin-17
• Mesenchymal stem cells
• Osteoblast
• Bone
• Osteogenesis
• Inflammation

Keel is an essential structural bone, providing anchorage for the attachment of large breast muscles in birds, allowing them to flap wings and provide proper ventilation for their lungs during flight. Previous studies reported that keel bone damage (especially fractures) negatively affects the welfare, health, production performance, eggshell quality, and mobility of laying hens contained in different housing systems. Furthermore, various factors affect keel bone damage, including nutrition, age, housing systems, and strains of laying hens. However, studies on the effects of abnormal bone metabolism and development on keel bone damage in laying hens are limited. Therefore, this study aimed to investigate the impacts of bone metabolism and development status on keel bone damage by determining the levels of serum bone turnover markers in laying hens. The results showed that laying hens with impaired keel bone had significantly altered levels of serum Ca and P metabolism-related and osteoblast and osteoclast activity-related markers compared to those in laying hens with normal keel bone. Thus, these results indicated that abnormal bone metabolism before keel bone damage reflected by varying levels of serum bone turnover markers might be a pivotal factor causing keel bone damage in laying hens. Our results also provide new insights into the occurrence of keel bone damage in laying hens.

Keel bone damage negatively affects the welfare, production performance, egg quality, and mobility of laying hens. This study aimed to investigate whether abnormal bone metabolism causes keel bone damage in laying hens. Eighty Hy-line Brown laying hens were housed in eight furnished cages with 10 birds per cage and studied from 18 to 29 weeks of age (WOA). Accordingly, keel bone status was assessed at 18, 22, 25, and 29 WOA using the X-ray method, and the serum samples of laying hens with normal keel (NK), deviated keel (DK), and fractured keel (FK) that occurred at 29 WOA were collected across all the time-points. Subsequently, the serum samples were used to measure markers related to the metabolism of Ca and P and activities of osteoblast and osteoclast. The results showed that FK laying hens had lighter bodyweight than NK and DK birds throughout the trial (p < 0.05), while the keel bone length and weight were not different in NK, DK, and FK hens at 29 WOA (p > 0.05). Moreover, bone hematoxylin and eosin (H&E) staining and tartrate-resistant acid phosphatase (TRAP) staining indicated that damaged keel bone had evident pathological changes. In the FK hens, serum P level was reduced but serum 1,25-dihydroxy-vitamin D₃ (1,25-(OH)₂D₃) and 25-hydroxyvitamin D₃ (25-OHD₃) levels were elevated compared to NK hens (p < 0.05). Additionally, DK hens had higher levels of serum 1,25-(OH)₂D₃, parathyroid hormone (PTH) and calcitonin (CT), and lower level of serum 25-OHD₃ than the NK birds (p < 0.05). Furthermore, serum alkaline phosphatase (ALP), osteocalcin (OC), osteoprotegerin (OPG), TRAP, and corticosterone (CORT) levels were elevated in DK and FK hens compared to NK hens (p < 0.05). The levels of serum Ca, P, PTH, ALP, TRAP, OPG, OC, and CORT in laying hens fluctuated with the age of the birds. Generally, the results of this study indicate that keel bone damage, especially fractures, could be associated with abnormal bone metabolism in laying hens.

• bone health
• bone metabolism
• furnished cage
• keel bone damage
• laying hens

• GPIbα
• angiogenesis
• apoptosis
• integrin αvβ3
• metastasis
• von Willebrand factor

• Animals
• Apoptosis/physiology
• Endothelial Cells/metabolism
• Endothelium, Vascular/metabolism
• Hemostasis/physiology
• Humans
• Leukocytes/metabolism
• Myocytes, Smooth Muscle/metabolism
• Weibel-Palade Bodies/metabolism
• von Willebrand Factor/metabolism

• Biomarkers
• Cancer
• Diagnostic
• Pancreatic cancer
• Review

• Biomarkers, Tumor
• CA-19-9 Antigen
• Humans
• MicroRNAs
• Pancreatic Neoplasms/diagnosis
• Prognosis

Bones constitute organs that are engaged in constant self-remodelling. Osteoblast and osteoclast homeostasis during remodelling contribute to overall skeletal status. Orthodontics is a clinical discipline that involves the investigation and implementation of moving teeth through the bone. The application of mechanical force to the teeth causes an imbalance between osteogenesis and osteogenesis in alveolar bone, leading to tooth movement. Osteoimmunology comprises the crosstalk between the immune and skeletal systems that regulate osteoclast–osteoblast homeostasis. Interleukin- (IL-) 20, an IL-10 family member, is regarded as a proinflammatory factor for autoimmune diseases and has been implicated in bone loss disease. However, the mechanism by which IL-20 regulates osteoclast differentiation and osteoclastogenesis activation remains unclear. This study investigated the effects of IL-20 on osteoclast differentiation in a rat model; it explored the underlying molecular mechanism in vitro and the specific effects on orthodontic tooth movement in vivo.

For in vitro analyses, primary rat bone marrow-derived macrophages (BMMs) were prepared from Sprague–Dawley rats for osteoclast induction. After BMMs had been treated with combinations of recombinant IL-20 protein, siRNA, and plasmids, the expression levels of osteoclast-specific factors and signalling pathway proteins were detected through real-time polymerase chain reaction, western blotting, and immunofluorescence staining. For in vivo analyses, IL-20 was injected into the rat intraperitoneal cavity after the establishment of a rat orthodontic tooth movement (OTM) model. OTM distance was detected by Micro-CT and HE staining; the expression levels of protein were detected through immunofluorescence staining.

In vitro analyses showed that a low concentration of IL-20 promoted preosteoclast proliferation and osteoclastogenesis. However, a high concentration of IL-20 inhibited BMM proliferation and osteoclastogenesis. IL-20 knockdown decreased the expression of osteoclast specific-markers, while IL-20 overexpression increased the expression of osteoclast specific-markers. Furthermore, IL-20 regulated osteoclast differentiation through the OPG/RANKL/RANK pathway. Overexpression of IL-20 could significantly upregulate RANKL-mediated osteoclast differentiation and osteoclast specific-marker expression; moreover, RANKL/NF-κB/NFATc1 acted as downstream signalling molecule for IL-20. In vivo analysis showed that OTM speed was significantly increased after intraperitoneal injection of IL-20; additionally, mechanical stress sensing proteins were markedly activated.

IL-20 augments osteoclastogenesis and osteoclast-mediated bone erosion through the RANKL/NF-κB/NFATc1 signalling pathway. IL-20 inhibition can effectively reduce osteoclast differentiation and diminish bone resorption. Furthermore, IL-20 can accelerate orthodontic tooth movement and activate mechanical stress sensing proteins.

• Denosumab
• Immuno-oncology
• Osteoblasts
• Osteoclasts
• Receptor activator of NF-kB ligand (RANKL)
• Reverse signaling

• Animals
• Humans
• Japan
• Models, Biological
• Osteoclasts/metabolism
• Osteogenesis/physiology
• Osteoprotegerin/metabolism
• RANK Ligand/metabolism
• Receptor Activator of Nuclear Factor-kappa B/metabolism

Bone homeostasis, based on a tight balance between bone formation and bone degradation, is affected by infection. On one hand, some invading pathogens are capable of directly colonizing the bone, leading to its destruction. On the other hand, immune mediators produced in response to infection may dysregulate the deposition of mineral matrix by osteoblasts and/or the resorption of bone by osteoclasts. Therefore, bone loss pathologies may develop in response to infection, and their detection and treatment are challenging. Possible biomarkers of impaired bone metabolism during chronic infection need to be identified to improve the diagnosis and management of infection-associated osteopenia. Further understanding of the impact of infections on bone metabolism is imperative for the early detection, prevention, and/or reversion of bone loss. Here, we review the mechanisms responsible for bone loss as a direct and/or indirect consequence of infection.

• bone
• chronic inflammation
• infection
• mesenchymal stem cell
• osteoblasts
• osteoclasts

Acute myeloid leukaemia (AML) is a haematopoietic malignancy caused by a combination of genetic and epigenetic lesions. Activation of the oncoprotein FLT3 ITD (Fms-like tyrosine kinase with internal tandem duplications) represents a key driver mutation in 25–30% of AML patients. FLT3 is a class III receptor tyrosine kinase, which plays a role in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Mutant FLT3 ITD results in an altered signalling quality, which causes cell transformation. Recent evidence indicates an effect of FLT3 ITD on bone homeostasis in addition to haematological aberrations. Using gene expression data repositories of FLT3 ITD-positive AML patients, we identified activated cytokine networks that affect the formation of the haematopoietic niche by controlling osteoclastogenesis and osteoblast functions. In addition, aberrant oncogenic FLT3 signalling of osteogenesis-specific cytokines affects survival of AML patients and may be used for prognosis. Thus, these data highlight the intimate crosstalk between leukaemic and osteogenic cells within the osteohaematopoietic niche.

• FMS-like tyrosine kinase 3 (FLT3)
• acute myeloid leukaemia (AML)
• bone remodelling
• haematopoiesis
• haematopoietic niche
• osteoblast (OB)
• osteoblastogenesis
• osteoclast (OC)

• Animals
• Bone and Bones/pathology
• Cell Line, Tumor
• Cytokines/metabolism
• Gene Duplication
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Hematopoietic Stem Cells/metabolism
• Homeostasis
• Humans
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/pathology
• Mice
• Oncogenes
• Osteoblasts/metabolism
• Osteoblasts/pathology
• Osteoclasts/metabolism
• Osteoclasts/pathology
• Osteogenesis
• Prognosis
• RAW 264.7 Cells
• Signal Transduction
• fms-Like Tyrosine Kinase 3/genetics
• fms-Like Tyrosine Kinase 3/metabolism

Tianma Gouteng Decoction (TGD) is widely used in traditional Chinese medicine for the treatment of hypertension and its related complications, but its mechanisms remain incompletely defined. We now aim to assess the protective effect of TGD against cardiovascular damage and to investigate its characteristics and underlying mechanisms. Blood pressure was determined in TGD-treated spontaneously hypertensive rats (SHR) by noninvasive measurements. Echocardiography was performed to assess cardiac function and structure and sirius red staining to evaluate cardiac fibrosis, and the degree of vascular remodeling was evaluated. Additionally, vasoconstriction and relaxation factor expression changes were examined by means of ELISA. Protein expression changes were verified by western blot. Compared with untreated SHR, TGD-treated SHR exhibited cardiovascular traits more akin to those of the normotensive Wistar Kyoto (WKY) rats. That is, they had lower diastolic blood pressure, systolic blood pressure and mean BP, and increased expression of vasodilation factor. We also found that TGD reduces ventricular and vascular remodeling and improves cardiac function in SHR. Finally, we tested the antiapoptosis effect TGD exerts in SHR, ostensibly by upregulating the expression of OPG, TRAIL, and death receptor 5 (DR5) and downregulating caspases 8, 7, and 3. TRAIL may also exert antiapoptotic and prosurvival effects by upregulating AKT expression. Therefore, TGD may reverse cardiovascular remodeling in SHR by upregulating the expression of OPG and TRAIL, upregulating AKT, and inhibiting apoptosis, at least in part. For the first time, we have shown that OPG and TRAIL play complimentary cardioprotective roles in SHR.

• Bone metastasis
• Breast cancer
• Mammary gland
• Metastasis
• Prolactin
• Prolactin receptor

• association study
• blood pressure
• polymorphism
• rank and osteoprotegerin genes

• Blood Pressure/genetics
• Female
• Genome-Wide Association Study
• Humans
• Middle Aged
• Osteoprotegerin/blood
• Polymorphism, Single Nucleotide
• Receptor Activator of Nuclear Factor-kappa B/blood
• Spain

• Asthma
• Childhood
• Osteoprotegerin

RANKL and RANK are expressed in different cell types and tissues throughout the body. They were originally described for their essential roles in bone remodeling and the immune system but have subsequently been shown to provide essential signals from regulating mammary gland homeostasis during pregnancy to modulating tumorigenesis. The success of RANKL/RANK research serves as a paragon for translational research from the laboratory to the bedside. The case in point has been the development of Denosumab, a RANKL-blocking monoclonal antibody which has already helped millions of patients suffering from post-menopausal osteoporosis and skeletal related events in cancer. Here we will provide an overview of the pathway from its origins to its clinical relevance in disease, with a special focus on emerging evidence demonstrating the therapeutic value of targeting the RANKL/RANK/OPG axis not only in breast cancer but also as an addition to the cancer immunotherapy arsenal.

• Denosumab
• RANKL/RANK/OPG
• malignant tumor
• osteoimmunology
• targeted therapy

Aortic aneurysm refers to dilatation of the aorta due to loss of elasticity and degenerative weakening of its wall. A preventive role for osteoprotegerin (Opg) in the development of abdominal aortic aneurysm has been reported in the CaCl₂-induced aneurysm model, whereas Opg was found to promote suprarenal aortic aneurysm in the AngII-induced ApoE knockout mouse aneurysm model. To determine whether there is a common underlying mechanism to explain the impact of Opg deficiency on the vascular structure of the two aneurysm models, we analyzed suprarenal aortic tissue of 6-month-old ApoE^-/-Opg^-/- mice after AngII infusion for 28 days. Less aortic dissection and aortic lumen dilatation, more adventitial thickening, and higher expression of collagen I and Trail were observed in ApoE^-/-Opg^-/- mice relative to ApoE^-/-Opg^+/+ mice. An accumulation of α-smooth muscle actin and vimentin double-positive myofibroblasts was noted in the thickened adventitia of ApoE^-/-Opg^-/- mice. Our results suggest that fibrotic remodeling of the aorta induced by myofibroblast accumulation might be an important pathological event which tends to limit AngII-induced aortic dilatation in ApoE^-/-Opg^-/- mice.

• Adventitia/pathology
• Adventitia/physiology
• Angiotensin II/pharmacology
• Animals
• Aorta, Abdominal/pathology
• Aorta, Abdominal/physiology
• Aortic Aneurysm, Abdominal/pathology
• Apolipoproteins E/deficiency
• Apolipoproteins E/genetics
• Cholesterol/blood
• Collagen Type I/metabolism
• Disease Models, Animal
• Fibrosis
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myofibroblasts/cytology
• Myofibroblasts/metabolism
• Osteoprotegerin/deficiency
• Osteoprotegerin/genetics
• TNF-Related Apoptosis-Inducing Ligand/metabolism
• Up-Regulation/drug effects

• Grant-in-Aid for Scientific Research

• OPG
• RANK
• RANKL
• Superficial candidiasis
• Systemic candidiasis

• Case-control association
• Meta-analysis
• Multilocus association
• OPG
• Otosclerosis
• Polymorphisms

• Alleles
• Case-Control Studies
• Chromosome Mapping
• Epistasis, Genetic
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Loci
• Genetic Predisposition to Disease
• Haplotypes
• Humans
• Linkage Disequilibrium
• Male
• Models, Biological
• Odds Ratio
• Osteoprotegerin/genetics
• Otosclerosis/diagnosis
• Otosclerosis/genetics
• Polymorphism, Single Nucleotide
• Reelin Protein

• EPIGENOTOS Grant under the Tunisia/India agreement on science and technology cooperation
• Grant under the Tunisia/India agreement on science and technology cooperation

Osteoprotegerin (OPG) is a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily (TNFRSF11B), that was first characterized and named for its protective role in bone remodeling. In this context, OPG binds to another TNF superfamily member Receptor Activator of NF-kappaB Ligand (RANKL; TNFSF11) and blocks interaction with RANK (TNFRSF11A), preventing RANKL/RANK stimulation of osteoclast maturation, and bone breakdown. Further studies revealed that OPG protein is also expressed by tumor cells and led to investigation of the role of OPG in tumor biology. An increasing body of data has demonstrated that OPG modulates breast tumor behavior. Initially, research was focused on OPG in the bone microenvironment as a potential inhibitor of RANKL-driven osteolysis. More recently, attention has shifted to include OPG expression and interactions in the primary breast tumor independent of RANKL. In the primary tumor, OPG may interact with another TNF superfamily member, TNF-Related Apoptosis Inducing Ligand (TRAIL; TNFSF10) to prevent apoptosis induction. Additional interest in OPG in breast cancer has been stimulated by the tumor-promoting role of its binding partner RANKL in association with BRCA1 gene mutations. We and others have previously summarized the functional studies on OPG and breast cancer (1, 2). After basic research studies on the in vitro role for OPG (and RANKL) in breast cancer, the field now expands to assess the in vivo role for OPG by examining the correlation between OPG expression and breast cancer risk or patient prognosis. However, the data reported so far is conflicting, since OPG expression appears linked to both good and poor patient survival. In the current review we will summarize these studies. Our goal is to provide stimulus for further research to bridge the basic research findings and clinical data regarding OPG in breast cancer.

• TNF superfamily
• TNFRSF11B
• breast cancer
• osteoprotegerin (OPG)
• prognosis
• risk

• Bone
• Immune system
• OPG
• Organ development
• Osteoimmunology
• RANK
• RANKL
• Tumor

• Japan Society for the Promotion of Science
• Precursory Research for Embryonic Science and Technology
• Japan Agency for Medical Research and Development
• Daiichi Sankyo Foundation of Life Science
• Japan Rheumatism foundation
• Kanzawa Medical Research Foundation
• LIFE SCIENCE FOUNDATION OF JAPAN
• Lotte Research Promotion Grant
• Meiji Yasuda Life Foundation of Health and Welfare
• Mitsui Life Social Foundation
• Naito Foundation
• Nakatomi Foundation
• Ono Medical Research Foundation
• Secom Science and Technology Foundation
• Suzuken Memorial Foundation
• Takeda Science Foundation
• Asahi Glass Foundation
• Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
• Sumitomo Foundation
• Uehara Memorial Foundation
• Tokyo Medical and Dental University

• Bone
• Metastasis
• Multiple myeloma
• OPG
• Osteosarcoma
• RANKL
• TRAIL

• Bone mass
• Colony stimulating factors
• Cytokines
• Interleukins
• Osteoblasts
• Osteoclasts

• augmentation
• bone regeneration
• dentistry
• immunology
• infammation
• lymphocytes
• mouse model
• osseointegration
• osteoimmunology
• osteomicrobiology
• periodontitis

There are accumulating studies reporting that vitamin E in general exhibits bone protective effects. This systematic review, however discusses the effects of a group of vitamin E isomers, tocotrienols in preventing bone loss through osteoclast differentiation and activity suppression.

This review is aimed to discuss the literature reporting the effects of tocotrienols on osteoclasts, the cells specialized for resorbing bone.

Out of the total 22 studies from the literature search, only 11 of them were identified as relevant, which comprised of eight animal studies, two in vitro studies and only one combination of both. The in vivo studies indicated that tocotrienols improve the bone health and reduce bone loss via inhibition of osteoclast formation and resorption activity, which could be through regulation of RANKL and OPG expression as seen from their levels in the sera. This is well supported by data from the in vitro studies demonstrating the suppression of osteoclast formation and resorption activity following treatment with tocotrienol isomers.

Thus, tocotrienols are suggested to be potential antioxidants for prevention and treatment of bone-related diseases characterized by increased bone loss.

• Osteoclast
• anti oxidants
• bone loss
• osteoblasts
• osteoclast
• tocotrienols.