116 results on '"Gabet Y"'
Search Results
2. Intrauterine stress induces bone loss in adult offspring of C3H/HeJ mice having high bone mass phenotype but not C57BL/6J mice with low bone mass phenotype
- Author
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Raygorodskaya, M., Gabet, Y., Shochat, C., Kobyliansky, E., Torchinsky, A., and Karasik, D.
- Published
- 2016
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3. A computerized model for reconstruction of dental ontogeny: A new tool for studying evolutionary trends in the dentition
- Author
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Smith, P., Müller, R., Gabet, Y., Avishai, G., Bailey, Shara E., editor, and Hublin, Jean-Jacques, editor
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- 2007
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4. Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells
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Baniwal, S. K., Shah, P. K., Shi, Y., Haduong, J. H., DeClerck, Y. A., Gabet, Y., and Frenkel, B.
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- 2012
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5. Bone-anabolic treatment enhances implantion: shifting critical strains to bone-implant interface: 054
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Kohavi, D, Gabet, Y, Voide, R, Müller, T, MÜLIer, R, and Bab, I
- Published
- 2007
6. Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children
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Gozes, I, Van Dijck, A, Hacohen-Kleiman, G, Grigg, I, Karmon, G, Giladi, E, Eger, M, Gabet, Y, Pasmanik-Chor, M, Cappuyns, E, Elpeleg, O, Kooy, R F, and Bedrosian-Sermone, S
- Subjects
0301 basic medicine ,Male ,Autism Spectrum Disorder ,Developmental Disabilities ,Nerve Tissue Proteins ,Mandible ,Tooth Eruption ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Animals ,Humans ,Tooth, Deciduous ,Biological Psychiatry ,Homeodomain Proteins ,Gene Expression Regulation, Developmental ,Infant ,X-Ray Microtomography ,Psychiatry and Mental health ,030104 developmental biology ,Mutation ,Original Article ,Female ,Human medicine ,Corrigendum ,Tooth ,030217 neurology & neurosurgery - Abstract
A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent neuroprotective protein (ADNP) is a most frequent de novo mutated ASD-related gene. Functionally, ADNP protects nerve cells against electrical blockade. In mice, complete Adnp deficiency results in dysregulation of over 400 genes and failure to form a brain. Adnp haploinsufficiency results in cognitive and social deficiencies coupled to sex- and age-dependent deficits in the key microtubule and ion channel pathways. Here, collaborating with parents/caregivers globally, we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. Looking at Adnp-deficient mice, by computed tomography, showed significantly smaller dental sacs and tooth buds at 5 days of age in the deficient mice compared to littermate controls. There was only trending at 2 days, implicating age-dependent dysregulation of teething in Adnp-deficient mice. Allen Atlas analysis showed Adnp expression in the jaw area. RNA sequencing (RNAseq) and gene array analysis of human ADNP-mutated lymphoblastoids, whole-mouse embryos and mouse brains identified dysregulation of bone/nervous system-controlling genes resulting from ADNP mutation/deficiency (for example, BMP1 and BMP4). AKAP6, discovered here as a major gene regulated by ADNP, also links cognition and bone maintenance. To the best of our knowledge, this is the first time that early primary (deciduous) teething is related to the ADNP syndrome, providing for early/simple diagnosis and paving the path to early intervention/specialized treatment plan.
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- 2017
7. Erratum: Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children
- Author
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Gozes, I, primary, Van Dijck, A, additional, Hacohen-Kleiman, G, additional, Grigg, I, additional, Karmon, G, additional, Giladi, E, additional, Eger, M, additional, Gabet, Y, additional, Pasmanik-Chor, M, additional, Cappuyns, E, additional, Elpeleg, O, additional, Kooy, R F, additional, and Bedrosian-Sermone, S, additional
- Published
- 2017
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8. A Validated Method for Titanium Implant Anchorage Analysis using MicroCT and Biomechanical Testing
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GABET, Y, primary and BAB, I, additional
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- 2015
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9. Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells
- Author
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Baniwal, S. K., primary, Shah, P. K., additional, Shi, Y., additional, Haduong, J. H., additional, DeClerck, Y. A., additional, Gabet, Y., additional, and Frenkel, B., additional
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- 2011
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10. Skeletal anabolic activity of cannabinoid receptor agonists
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Ofek, O., primary, Goldfine, L., additional, Bajayo, A., additional, Melamed, E., additional, Gabet, Y., additional, Shohami, E., additional, Mechoulam, R., additional, and Bab, I., additional
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- 2009
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11. A computerized model for reconstruction of dental ontogeny: A new tool for studying evolutionary trends in the dentition.
- Author
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Delson, Eric, MacPhee, Ross D.E., Conard, Nicholas, Fleagle, John G., McBrearty, Sally, Meng, Jin, Plummer, Tom, Rogers, Kristi Curry, Rose, Ken, Bailey, Shara E., Hublin, Jean-Jacques, Smith, P., Müller, R., Gabet, Y., and Avishai, G.
- Abstract
All hominid molars show the same sequence of cusp initiation, but differ in the later stages of development. The topography of the dentin-enamel junction (DEJ) represents the outcome of differential growth between cusps. Since the cusps grow in an orderly sequence from tip to base (defined by the plane of coalescence with adjacent cusps), quantification of cusp volume and relationships can be used to reconstruct successive stages in development and their contribution to the morphometry of the crown surface. Their volume and spatial relationships at the DEJ enable us to partition cell proliferation in relation to cusp initiation, while quantification of the amount and distrib ution of enamel overlying the DEJ provides the necessary discrimination between cell proliferation and cell function, expressed in enamel matrix apposition. We have developed a three-dimensional computerized model of a lower molar tooth that enables us to identify and quantify the different stages of tooth development defined above. The model is based on serial micro-computed tomography (microCT) images of human teeth that provide accurate quantification of the outer and inner enamel and dentin boundaries of individual cusps. We have used this model to compare morphogenesis in the lower second deciduous molar and lower first permanent molar. Spatial relationships of the cusps, expressed by the topography of the DEJ showed that shape differences were established in the early stages of morphogenesis by differential proliferation within the developing tooth germ and that cusp size and proportions were modified at the crown surface by enamel apposition. Reduction of the hypoconulid in the permanent molar shown at the DEJ was largely masked by the exceptional thickness of enamel on this cusp. We propose that this model provides a novel contribution to the identification of ontogenetic trajectories and their contribution to evolutionary trends in tooth size, shape and enamel thickness. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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12. Essai de justification anatom ique et électromyographique du rôle du muscle vaste medial dans la genèse d'arthropathies fémoropatellaires
- Author
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Galtier, B, primary, Guillot, M, additional, Nimzline, B, additional, and Gabet, Y, additional
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- 1996
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13. Innervation modes of the vastus medialis and femoropatellar arthrosis
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Galtier, B., Guillot, M., Nimzline, B., and Gabet, Y.
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- 1996
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14. Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis
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Gabet Yankel, Khalid Omar, Baniwal Sanjeev K, Shah Ruchir R, Purcell Daniel J, Mav Deepak, Kohn-Gabet Alice E, Shi Yunfan, Coetzee Gerhard A, and Frenkel Baruch
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Prostate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome wide mRNA expression changes in PCa cells in response to Runx2. Results We engineered a C4-2B PCa sub-line called C4-2B/Rx2dox, in which Doxycycline (Dox) treatment stimulates Runx2 expression from very low to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal. Conclusions The effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways.
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- 2010
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15. Endocannabinoid Signaling Regulates Bone Mass.
- Author
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Ofek, O., Karsak, M., Fogel, M., Wright, K., Tam, Y., Gabet, Y., Birenboim, R., Attar-Namdar, M., Shohami, E., Mechoulam, R., Zimmer, A., and Bab, I.
- Published
- 2005
16. Clinical potential of plasma-functionalized graphene oxide ultrathin sheets for bone and blood vessel regeneration: Insights from cellular and animal models.
- Author
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Krukiewicz K, Contessotto P, Nedjari S, Martino MM, Redenski I, Gabet Y, Speranza G, O'Brien T, Altankov G, and Awaja F
- Subjects
- Animals, Humans, Rats, Osteogenesis drug effects, Osteogenesis physiology, Mice, Blood Vessels, Rats, Sprague-Dawley, Bone and Bones blood supply, Bone and Bones drug effects, Plasma Gases pharmacology, Plasma Gases chemistry, Tibia blood supply, Neovascularization, Physiologic drug effects, Tissue Engineering methods, Graphite chemistry, Bone Regeneration drug effects, Bone Regeneration physiology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Human Umbilical Vein Endothelial Cells
- Abstract
Graphene and graphene oxide (GO), due to their unique chemical and physical properties, possess biochemical characteristics that can trigger intercellular signals promoting tissue regeneration. Clinical applications of thin GO-derived sheets have inspired the development of various tissue regeneration and repair approaches. In this study, we demonstrate that ultrathin sheets of plasma-functionalized and reduced GO, with the oxygen content ranging from 3.2 % to 22 % and the nitrogen content from 0 % to 8.3 %, retain their essential mechanical and molecular integrity, and exhibit robust potential for regenerating bone tissue and blood vessels across multiple cellular and animal models. Initially, we observed the growth of blood vessels and bone tissue in vitro using these functionalized GO sheets on human adipose-derived mesenchymal stem cells and umbilical vein endothelial cells. Remarkably, our study indicates a 2.5-fold increase in mineralization and two-fold increase in tubule formation even in media lacking osteogenic and angiogenic supplements. Subsequently, we observed the initiation, conduction, and formation of bone and blood vessels in a rat tibial osteotomy model, evident from a marked 4-fold increase in the volume of low radio-opacity bone tissue and a significant elevation in connectivity density, all without the use of stem cells or growth factors. Finally, we validated these findings in a mouse critical-size calvarial defect model (33 % higher healing rate) and a rat skin lesion model (up to 2.5-fold increase in the number of blood vessels, and 35 % increase in blood vessels diameter). This study elucidates the pro-osteogenic and pro-angiogenic properties of both pristine and plasma-treated GO ultrathin films. These properties suggest their significant potential for clinical applications, and as valuable biomaterials for investigating fundamental aspects of bone and blood vessel regeneration., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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17. A perspective on muscle phenotyping in musculoskeletal research.
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Foessl I, Ackert-Bicknell CL, Kague E, Laskou F, Jakob F, Karasik D, Obermayer-Pietsch B, Alonso N, Bjørnerem Å, Brandi ML, Busse B, Calado Â, Cebi AH, Christou M, Curran KM, Hald JD, Semeraro MD, Douni E, Duncan EL, Duran I, Formosa MM, Gabet Y, Ghatan S, Gkitakou A, Hassler EM, Högler W, Heino TJ, Hendrickx G, Khashayar P, Kiel DP, Koromani F, Langdahl B, Lopes P, Mäkitie O, Maurizi A, Medina-Gomez C, Ntzani E, Ohlsson C, Prijatelj V, Rabionet R, Reppe S, Rivadeneira F, Roshchupkin G, Sharma N, Søe K, Styrkarsdottir U, Szulc P, Teti A, Tobias J, Valjevac A, van de Peppel J, van der Eerden B, van Rietbergen B, Zekic T, and Zillikens MC
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- Animals, Humans, Muscle, Skeletal metabolism, Zebrafish, Mice, Sarcopenia metabolism, Sarcopenia physiopathology, Musculoskeletal Diseases physiopathology, Musculoskeletal Diseases genetics, Osteoporosis metabolism, Osteoporosis pathology, Phenotype
- Abstract
Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse., Competing Interests: Declaration of interests No interests are declared., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)
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- 2024
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18. S-Allylmercapto-N-Acetylcysteine (ASSNAC) Attenuates Osteoporosis in Ovariectomized (OVX) Mice.
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Bleichman I, Hiram-Bab S, Gabet Y, and Savion N
- Abstract
Osteoporosis is a bone-debilitating disease, demonstrating a higher prevalence in post-menopausal women due to estrogen deprivation. One of the main mechanisms underlying menopause-related bone loss is oxidative stress. S -allylmercapto- N -acetylcysteine (ASSNAC) is a nuclear factor erythroid 2-related factor 2 (Nrf2) activator and cysteine supplier, previously shown to have anti-oxidation protective effects in cultured cells and animal models. Here, we studied the therapeutic potential of ASSNAC with and without Alendronate in ovariectomized (OVX) female mice. The experimental outcome included (i) femur and L3 lumbar vertebra morphometry via Micro-Computed Tomography (μCT); (ii) bone remodeling (formation vs. resorption); and (iii) oxidative stress markers in bone marrow (BM) cells. Four weeks after OVX, there was a significant bone loss that remained evident after 8 weeks, as demonstrated via µCT in the femur (cortical and trabecular bone compartments) and vertebra (trabecular bone). ASSNAC at a dose of 50 mg/Kg/day prevented bone loss after the four-week treatment but had no significant effect after 8 weeks, while ASSNAC at a dose of 20 mg/Kg/day significantly protected against bone loss after 8 weeks of treatment. Alendronate prevented ovariectomy-induced bone loss, and combining it with ASSNAC further augmented this effect. OVX mice demonstrated high serum levels of both C-terminal cross-linked telopeptides of type I collagen (CTX) (bone resorption) and procollagen I N-terminal propeptide (P1NP) (bone formation) after 2 weeks, and these returned to control levels after 8 weeks. Alendronate, ASSNAC and their combination decreased CTX and increased P1NP. Alendronate induced oxidative stress as reflected by decreased glutathione and increased malondialdehyde (MDA) levels, and combining it with ASSNAC partially attenuated these changes. These results portray the therapeutic potential of ASSNAC for the management of post-menopausal osteoporosis. Furthermore, ASSNAC ameliorates the Alendronate-associated oxidative stress, suggesting its potential to prevent Alendronate side effects as well as improve its bone-protective effect.
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- 2024
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19. Therapeutic Potential of Cannabidiol and Cannabigerol in Fracture Healing.
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Gabet Y
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- Fracture Healing, Cannabidiol pharmacology, Cannabidiol therapeutic use, Cannabinoids pharmacology, Cannabinoids therapeutic use, Cannabis
- Published
- 2023
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20. A study of the influence of genetic variance and sex on the density and thickness of the calvarial bone in collaborative cross mice.
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Kaspersky U, Levy R, Nashef A, Iraqi FA, and Gabet Y
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- Male, Female, Mice, Animals, X-Ray Microtomography, Genotype, Phenotype, Collaborative Cross Mice, Bone and Bones
- Abstract
Background: Bone microarchitecture is affected by multiple genes, each having a small effect on the external appearance. It is thus challenging to characterize the genes and their specific effect on bone thickness and porosity. The purpose of this study was to assess the heritability and the genetic variation effect, as well as the sex effect on the calvarial bone thickness (Ca.Th) and calvarial porosity (%PoV) using the Collaborative Cross (CC) mouse population., Methods: In the study we examined the parietal bones of 56 mice from 9 lines of CC mice. Morphometric parameters were evaluated using microcomputed tomography (μCT) and included Ca.Th and %PoV. We then evaluated heritability, genetic versus environmental variance and the sex effect for these parameters., Results: Our morphometric analysis showed that Ca.Th and %PoV are both significantly different among the CC lines with a broad sense heritability of 0.78 and 0.90, respectively. The sex effect within the lines was significant in line IL111 and showed higher values of Ca.Th and %PoV in females compared to males. In line IL19 there was a borderline sex effect in Ca.Th in which males showed higher values than females., Conclusions: These results stress the complexity of sex and genotype interactions controlling Ca.Th and %PoV, as the skeletal sexual dimorphism was dependent on the genetic background. This study also shows that the CC population is a powerful tool for establishing the genetic effect on these traits., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)
- Published
- 2023
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21. The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Non-Melanoma Skin Cancer.
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Iden JA, Raphael-Mizrahi B, Naim A, Kolomansky A, Liron T, Neumann D, Vered M, and Gabet Y
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- Animals, Mice, 9,10-Dimethyl-1,2-benzanthracene toxicity, Carcinogenesis genetics, Carcinogenesis pathology, Carcinogens toxicity, Receptors, Cannabinoid, Skin pathology, Tetradecanoylphorbol Acetate toxicity, Tumor Microenvironment, Papilloma pathology, Skin Neoplasms chemically induced, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to systemic CB2 knockout (CB2
-/- ) mice, we performed a spontaneous cancer study in one-year old mice, and subsequently used the multi-stage chemical carcinogenesis model, wherein cancer is initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that aging CB2-/- mice have an increased incidence of spontaneous cancerous and precancerous skin lesions compared to their WT counterparts. In the DMBA/TPA model, CB2-/- developed more and larger papillomas, had decreased spontaneous regression of papillomas, and displayed an altered systemic immune profile, including upregulated CD4+ T cells and dendritic cells, compared to WT mice. Immune cell infiltration in the tumor microenvironment was generally low for both genotypes, although a trend of higher myeloid-derived suppressor cells was observed in the CB2-/- mice. CB2 expression in carcinogen-exposed skin was significantly higher compared to naïve skin in WT mice, suggesting a role of CB2 on keratinocytes. Taken together, our data show that endogenous CB2 activation plays an anti-tumorigenic role in non-melanoma skin carcinogenesis, potentially via an immune-mediated response involving the alteration of T cells and myeloid cells coupled with the modulation of keratinocyte activity.- Published
- 2023
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22. The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer: A Study in Mice and Humans.
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Iden JA, Raphael-Mizrahi B, Awida Z, Naim A, Zyc D, Liron T, Kasher M, Livshits G, Vered M, and Gabet Y
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- Animals, Humans, Mice, Mice, Knockout, Prognosis, Carcinogenesis genetics, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Receptor, Cannabinoid, CB2 genetics, Receptor, Cannabinoid, CB2 metabolism
- Abstract
The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer. Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2
-/- ) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (ApcMin/+ ). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence. Aging CB2-/- mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2-/- and ApcMin/+ CB2-/- mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans. Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients.- Published
- 2023
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23. The results of a unique dietary supplement (nutraceutical formulation) used to treat the symptoms of long-haul COVID.
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Gaylis NB, Kreychman I, Sagliani J, Mograbi J, and Gabet Y
- Abstract
Long-COVID is a syndrome characterized by debilitating symptoms that persist over 3 months after infection with the SARS-CoV-2 virus. It affects 15 to 33% of COVID-19 recovered patients and has no dedicated treatment. First, we found that β-caryophyllene and pregnenolone have a significant synergistic effect in the resolution of LPS-induced sepsis and inflammation in mice. Then we combined these two compounds with seven others and designed a unique dietary supplement formulation to alleviate long COVID inflammatory and neurological disorders. We performed a one-arm open-labeled study at a single site with 51 eligible patients from 18 states. Each participant recorded the severity level of 12 symptoms (including fatigue, weakness, cardiac and neurological symptoms, shortness of breath, gastrointestinal disorders, ageusia or anosmia, anxiety, joint pain, rash, cough, and insomnia) at baseline, 2- and 4-week time points. On average, all the symptoms were significantly milder after 2 weeks, with further improvement after 4 weeks. Importantly, each symptom was significantly attenuated in 72 to 84% of the participants. There were no significant adverse effects. Our data indicate that the use of this nutraceutical product is a safe and significantly efficient option to reduce multiple symptoms of long COVID., Competing Interests: The clinical study has been sponsored in part by NTN Enterprises LLC. Authors NG and JM own stock in NTN Enterprises LLC. Ramot, the technology transfer company of Tel Aviv University also owns stock in this company, and YG was an employee of Tel Aviv University. Authors JM and YG are the inventors of patent PCT/IL2022/050676, which exclusive rights has been acquired by NTN Enterprises LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gaylis, Kreychman, Sagliani, Mograbi and Gabet.)
- Published
- 2022
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24. Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice.
- Author
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Awida Z, Hiram-Bab S, Bachar A, Saed H, Zyc D, Gorodov A, Ben-Califa N, Omari S, Omar J, Younis L, Iden JA, Graniewitz Visacovsky L, Gluzman I, Liron T, Raphael-Mizrahi B, Kolomansky A, Rauner M, Wielockx B, Gabet Y, and Neumann D
- Subjects
- Animals, Female, Mice, Osteoblasts metabolism, Osteoclasts metabolism, Signal Transduction, Erythropoietin metabolism, Erythropoietin pharmacology, Receptors, Erythropoietin genetics, Receptors, Erythropoietin metabolism
- Abstract
Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating a contribution by EPOR on other cell lineages. This study was designed to define the role of monocyte EPOR in EPO-mediated bone loss, by using two mouse lines with conditional deletion of EPOR in the monocytic lineage. Low-dose EPO attenuated the reduction in bone volume (BV/TV) in Cx3cr1
Cre EPORf/f female mice (27.05%) compared to controls (39.26%), but the difference was not statistically significant. To validate these findings, we increased the EPO dose in LysMCre model mice, a model more commonly used to target preosteoclasts. There was a significant reduction in both the increase in the proportion of bone marrow preosteoclasts (CD115+ ) observed following high-dose EPO administration and the resulting bone loss in LysMCre EPORf/f female mice (44.46% reduction in BV/TV) as compared to controls (77.28%), without interference with the erythropoietic activity. Our data suggest that EPOR in the monocytic lineage is at least partially responsible for driving the effect of EPO on bone mass.- Published
- 2022
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25. S -allylmercapto- N -acetylcysteine protects bone cells from oxidation and improves femur microarchitecture in healthy and diabetic mice.
- Author
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Abu-Kheit R, Kotev-Emeth S, Hiram-Bab S, Gabet Y, and Savion N
- Subjects
- Acetylcysteine analogs & derivatives, Allyl Compounds, Animals, Bone Density, Female, Femur, Glutathione, Mice, Mice, Inbred C57BL, Neutral Red pharmacology, Obesity, Rats, Reactive Oxygen Species, X-Ray Microtomography methods, Antioxidants pharmacology, Diabetes Mellitus, Experimental drug therapy
- Abstract
Oxidative stress is involved in the deterioration of bone quality and mechanical strength in both diabetic and aging adults. Therefore, we studied the ability of the antioxidant compound, S -allylmercapto- N -acetylcysteine (ASSNAC) to protect bone marrow stromal cells (BMSCs) from advanced glycation end-products (AGEs) cytotoxicity and improve bone microarchitecture of adult healthy and obese/diabetic (db/db) female mice. ASSNAC effect on AGEs-treated cultured rat BMSCs was evaluated by Neutral Red and XTT cell survival and reactive oxygen species (ROS) level assays. Its effect on healthy (C57BL/6) and obese/diabetic (C57BLKS/J Lepr
db+/+ ; db/db) female mice femur parameters, such as (1) number of adherent BMSCs, (2) percentage of CD73+ /CD45- cells in bone marrow (BM), (3) glutathione level in BM cells, and (4) femur microarchitecture parameters by microcomputed tomography, was studied. ASSNAC treatment protected BMSCs by significantly decreasing AGEs-induced ROS production and increasing their cellular resistance to the cytotoxic effect of AGEs. ASSNAC treatment of healthy female mice (50 mg/kg/day; i.p.; age 12-20 weeks) significantly increased the number of BMSCs (+60%), CD73+ /CD45- cells (+134%), and glutathione level (+110%) in the femur bone marrow. Furthermore, it increased the femur length (+3%), cortical diameter (+3%), and cortical areal moment of inertia (Ct.MOI; +10%) a surrogate for biomechanical strength. In db/db mice that demonstrated a compromised trabecular bone and growth plate microarchitecture, ASSNAC treatment restored the trabecular number (Tb.N, +29%), bone volume fraction (Tb.BV/TV, +130%), and growth plate primary spongiosa volumetric bone mineral density (PS-vBMD, +7%) and thickness (PS-Th, +18%). In conclusion, this study demonstrates that ASSNAC protects bone marrow cells from oxidative stress and may improve bone microarchitecture in adult healthy and diabetic female mice.- Published
- 2022
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26. Osteogenic growth peptide is a potent anti-inflammatory and bone preserving hormone via cannabinoid receptor type 2.
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Raphael-Mizrahi B, Attar-Namdar M, Chourasia M, Cascio MG, Shurki A, Tam J, Neuman M, Rimmerman N, Vogel Z, Shteyer A, Pertwee RG, Zimmer A, Kogan NM, Bab I, and Gabet Y
- Subjects
- Animals, Female, Hormones, Humans, Mice, Osteoporosis drug therapy, Osteoporosis metabolism, Osteoporosis prevention & control, Peptides metabolism, Histones metabolism, Histones pharmacology, Intercellular Signaling Peptides and Proteins metabolism, Intercellular Signaling Peptides and Proteins pharmacology, Osteogenesis physiology, Receptor, Cannabinoid, CB2 metabolism
- Abstract
The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as osteogenic growth peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse models and cells, and in human osteoblasts. We show that the OGP effects on osteoblast proliferation, osteoclastogenesis, and macrophage inflammation in vitro, as well as rescue of ovariectomy-induced bone loss and prevention of ear edema in vivo are all abrogated by genetic or pharmacological ablation of CB2. We also demonstrate that OGP binds at CB2 and may act as both an agonist and positive allosteric modulator in the presence of other lipophilic agonists. In premenopausal women, OGP circulating levels significantly decline with age. In adult mice, exogenous administration of OGP completely prevented age-related bone loss. Our findings suggest that OGP attenuates age-related bone loss by maintaining a skeletal CB2 tone. Importantly, they also indicate the occurrence of an endogenous peptide that signals via CB2 receptor in health and disease., Competing Interests: BR, MA, MC, MC, AS, JT, MN, NR, ZV, AS, RP, AZ, NK, IB, YG No competing interests declared, (© 2022, Raphael-Mizrahi et al.)
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- 2022
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27. Orthodontic force and extracorporeal shock wave therapy: Assessment of orthodontic tooth movement and bone morphometry in a rat model.
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Hazan-Molina H, Gabet Y, Aizenbud I, Aizenbud N, and Aizenbud D
- Subjects
- Animals, Osteoclasts, Osteogenesis, Rats, Vascular Endothelial Growth Factor A, X-Ray Microtomography, Extracorporeal Shockwave Therapy, Tooth Movement Techniques
- Abstract
Objective: The objective was to investigate the effect of extracorporeal shock wave therapy (ESWT) on the magnitude of orthodontic tooth movement, in a rat model, based on a previously established treatment protocol., Design: In conjunction with orthodontic force commencement, rats underwent ESWT. The amount of tooth movement along with different microarchitectural parameters were measured after three weeks by means of microcomputed tomography. In addition, the percentage of cells expressing vascular endothelial growth factor, the number of tartrate-resistant acid phosphatase (TRAP) positive cells/area and blood vessel density were evaluated both for the pressure and tension sides., Results: The addition of ESWT to the orthodontic force after three weeks more than doubled the average tooth movement. The addition of ESWT on the pressure side induced a significant decrease in volumetric bone mineral density. Blood vessel density and the number of TRAP positive cells were higher after the application of ESWT., Conclusion: The induction of ESWT during orthodontic tooth movement in a rat model increases the rate of tooth movement by accelerating bone resorption on the pressure side and possibly enhances bone formation on the tension side., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2022
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28. Microcomputed Tomography-Based Analysis of Neovascularization within Bioengineered Vascularized Tissues.
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Redenski I, Guo S, Machour M, Szklanny A, Landau S, Egozi D, Gabet Y, and Levenberg S
- Subjects
- Adipose Tissue diagnostic imaging, Animals, Rats, Tissue Engineering, X-Ray Microtomography, Endothelial Cells, Mesenchymal Stem Cells
- Abstract
In the field of tissue engineering, evaluating newly formed vascular networks is considered a fundamental step in deciphering the processes underlying tissue development. Several common modalities exist to study vessel network formation and function. However, a proper methodology that allows through three-dimensional visualization of neovessels in a reproducible manner is required. Here, we describe in-depth exploration, visualization, and analysis of vessels within newly formed tissues by utilizing a contrast agent perfusion protocol and high-resolution microcomputed tomography. Bioengineered constructs consisting of porous, biocompatible, and biodegradable scaffolds are loaded with cocultures of adipose-derived microvascular endothelial cells (HAMECs) and dental pulp stem cells (DPSCs) and implanted in a rat femoral bundle model. After 14 days of in vivo maturation, we performed the optimized perfusion protocol to allow host penetrating vascular visualization and assessment within neotissues. Following high-resolution microCT scanning of DPSC:HAMEC explants, we performed the volumetric and spatial analysis of neovasculature. Eventually, the process was repeated with a previously published coculture system for prevascularization based on adipose-derived mesenchymal stromal cells (MSCs) and HAMECs. Overall, our approach allows a comprehensive understanding of vessel organization during engraftment and development of neotissues.
- Published
- 2022
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29. The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice.
- Author
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Awida Z, Bachar A, Saed H, Gorodov A, Ben-Califa N, Ibrahim M, Kolomansky A, Iden JA, Graniewitz Visacovsky L, Liron T, Hiram-Bab S, Brines M, Gabet Y, and Neumann D
- Subjects
- Animals, Cell Differentiation drug effects, Cells, Cultured, Female, Hematopoiesis drug effects, Mice, Mice, Inbred C57BL, Osteoclasts drug effects, Osteoclasts metabolism, Bone Density drug effects, Erythropoietin metabolism, Oligopeptides pharmacology, Osteogenesis drug effects
- Abstract
The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin
- CD11b- Ly6Chi CD115+ , by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.- Published
- 2021
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30. Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice.
- Author
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de Castro LF, Sworder BJ, Mui B, Futrega K, Berendsen A, Phillips MD, Burbach NJ, Cherman N, Kuznetsov S, Gabet Y, Holmbeck K, and Robey PG
- Abstract
In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived "mesenchymal stem cells"), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic bone formation assay. SFRPs modulate WNT signaling, which is essential to maintain skeletal homeostasis, but the specific role of SFRP2 in BMSCs/SSCs is unclear. Here, we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and regeneration. The skeleton of Sfrp2-deficient (KO) mice is overtly normal; but their BMSCs/SSCs exhibit reduced colony-forming efficiency, reflecting low SSC self-renewal/abundancy. Sfrp2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation assay. Moreover, regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO mice. Sfrp2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium accumulation. Interestingly, activation of the Wnt co-receptor, Lrp6, and expression of Wnt target genes, Axin2, C-myc and Cyclin D1, were reduced in Sfrp2-deficient BMSCs/SSCs. Addition of recombinant Sfrp2 restored most of these activities, suggesting that Sfrp2 acts as a Wnt agonist. We demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone healing. SFRP2 is also a useful marker of BMSC/SSC multipotency, and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products., (© 2021. The Author(s).)
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- 2021
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31. Analytical methodology to measure periodontal bone morphometry following orthodontic tooth movement in mice.
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Fleissig O, Hazan-Molina H, Chaushu S, Aizenbud D, Klein Y, Zini A, and Gabet Y
- Subjects
- Animals, Bone Remodeling, Humans, Mice, Periodontal Ligament diagnostic imaging, X-Ray Microtomography, Osteoclasts, Tooth Movement Techniques methods
- Abstract
Introduction: Basic research in orthodontics is commonly conducted in rodents. However, experimental studies on orthodontic tooth movement (OTM) lack a standard method to examine OTM and periodontal changes. This study describes a unifying protocol for the analysis of OTM and associated bone microarchitectural changes in mice using microcomputed tomography (µCT)., Methods: Mice (10 animals/group) were divided into control and OTM groups. OTM was generated by anchoring a nickel-titanium closed-coil spring to the upper incisors to pull the upper left first molar. A third group of TNFα -/- mice was added since these are known to have slower OTM. Using µCT, we implemented and tested a number of methods to measure OTM distance and examine 3D bone morphometric parameters associated with OTM in mice., Results: In total, we tested five methods to measure the OTM distance in mice. The results indicated that measuring the intermolar diastema, and assessing tooth movement relative to the anterior root of the zygomatic arch, displayed the lowest standard deviation and enabled optimal detection of intergroup differences. We also developed two protocols for µCT analysis of the periradicular bone that yielded no false-positive results. Our results revealed that including the width of the periodontal ligament rather than excluding it from the region of interest in mice detected more statistically significant differences in the morphometric parameters between the OTM and control sides and between WT and TNFα -/- mice despite more subtle differences., Conclusions: We, therefore, propose new guidelines for a standardized μCT-based method to analyse OTM and the extent of the periradicular bone structural changes in mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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32. Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques.
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Rauner M, Foessl I, Formosa MM, Kague E, Prijatelj V, Lopez NA, Banerjee B, Bergen D, Busse B, Calado Â, Douni E, Gabet Y, Giralt NG, Grinberg D, Lovsin NM, Solan XN, Ostanek B, Pavlos NJ, Rivadeneira F, Soldatovic I, van de Peppel J, van der Eerden B, van Hul W, Balcells S, Marc J, Reppe S, Søe K, and Karasik D
- Subjects
- Animals, Animals, Genetically Modified, Bone Diseases genetics, Bone Diseases metabolism, Bone Diseases pathology, Genetic Predisposition to Disease, Genome-Wide Association Study trends, Humans, Models, Animal, Multifactorial Inheritance genetics, Musculoskeletal Diseases metabolism, Musculoskeletal Diseases pathology, Phenotype, Quantitative Trait Loci, Systems Integration, Validation Studies as Topic, Genome-Wide Association Study methods, Musculoskeletal Diseases genetics
- Abstract
The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits ("endophenotypes"), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rauner, Foessl, Formosa, Kague, Prijatelj, Lopez, Banerjee, Bergen, Busse, Calado, Douni, Gabet, Giralt, Grinberg, Lovsin, Solan, Ostanek, Pavlos, Rivadeneira, Soldatovic, van de Peppel, van der Eerden, van Hul, Balcells, Marc, Reppe, Søe and Karasik.)
- Published
- 2021
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33. Different Effects of Soy and Whey on Linear Bone Growth and Growth Pattern in Young Male Sprague-Dawley Rats.
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Bar-Maisels M, Menahem C, Gabet Y, Hiram-Bab S, Phillip M, and Gat-Yablonski G
- Abstract
The aim of this investigation was to determine the better protein for supporting optimal linear growth, as the exact composition and benefits of specific dietary proteins in supporting linear growth is unknown. In the current study, we compared the effect of soy and whey proteins, both proteins contain all essential amino acids and are considered the best proteins in their categories. Young male rats were subjected to multiple feeding protocols using iso-energetic diets containing soy or whey as the sole protein source. The rats were allowed to eat ad libitum for 11, 24, or 74 days in the first set of experiments, and the soy group was pair-fed to the whey group in the second set. The differences in weight gain, food consumption, and humeri length of the soy group that were greater at the beginning of the ad libitum experiments lessened over time. Pair-fed experiments revealed that the increased weight and humeri length resulted from the differences in food consumption. However, other parameters were protein specific. Bone quality, which was better in the soy group at 24 days, was matched by the whey group and even surpassed that of the soy group in the long-term experiment, with a significantly greater bone mineral density, cortical thickness, and growth plate. Although in the short term the levels of insulin like growth factor (IGF)-I were similar between the groups, IGF-I increased with age in the whey group, and the levels at the long-term experiment were significantly higher compared to the soy group. Furthermore, using the pair fed setup made it clear that when the difference in food consumption were no longer playing part, whey was more efficient in increasing IGF-I. There were no indications of metabolic sequelae. Although the use of soy is gaining in popularity as a sustainable protein, our findings indicate a better effect of whey on linear growth by leading to slower growth with better-organized epiphyseal growth plates and bone quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bar-Maisels, Menahem, Gabet, Hiram-Bab, Phillip and Gat-Yablonski.)
- Published
- 2021
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34. The Balance between Orthodontic Force and Radiation in the Jawbone: Microstructural, Histological, and Molecular Study in a Rat Model.
- Author
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Dorchin-Ashkenazi H, Ginat-Koton R, Gabet Y, Klein Y, Chaushu S, Dorchin H, Brosh T, and Vered M
- Abstract
Irradiation of facial bones is associated with a lifelong risk of osteonecrosis. In a rat model, maxillae were exposed to a single 5 Gy dose of external beam radiation and orthodontic force was applied for 2 weeks on the first maxillary molar; control rats were treated identically without radiation. Tooth movement in irradiated jaws was 30% less than in controls, representing radiation-related damage. Micro-CT, histological, and molecular outcomes of orthodontic tooth movement were studied. Microstructurally, bone parameters (trabecular thickness, bone volume fraction, bone mineral density) were significantly affected by orthodontic force but not by radiation. Histological parameters were influenced only by orthodontic force, especially by an increase in osteoclasts. A molecular study revealed a differential distribution of cells expressing pre-osteoclast markers (RANK+-majority, CD11b+, CD14+-minority), with changes being influenced by orthodontic force (increased CD11b+ and CD14+ cells) and also by radiation (decreased RANK+ cells). The activation status of osteoclasts (TRAP staining) showed an orthodontic-force-related increase, which probably could not fully compensate for the radiation-associated impairment. The overall balance showed that orthodontic force had elicited a substantial microstructural, histological, and functional normalization process in irradiated maxillae but a radiation-induced impact was still conspicuous. Additional studies are needed to validate these findings.
- Published
- 2021
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35. Editorial: Developmental Biology and Regulation of Osteoclasts.
- Author
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Gabet Y, Neumann D, Levaot N, Elson A, and Sims NA
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2021
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36. Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss.
- Author
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Rauner M, Murray M, Thiele S, Watts D, Neumann D, Gabet Y, Hofbauer LC, and Wielockx B
- Abstract
High erythropoietin (Epo) levels are detrimental to bone health in adult organisms. Adult mice receiving high doses of Epo lose bone mass due to suppressed bone formation and increased bone resorption. In humans, high serum Epo levels are linked to fractures in elderly men. Our earlier studies indicated that Epo modulates osteoblast activity; however, direct evidence that Epo acts via its receptor (EpoR) on osteoblasts in vivo is still missing. Here, we created mice lacking EpoR in osteoprogenitor cells to specifically address this gap. Deletion of EpoR in osteoprogenitors (EpoR:Osx-cre, cKO) starting at 5 weeks of age did not alter red blood cell parameters but increased vertebral bone volume by 25% in 12-week-old female mice. This was associated with low bone turnover. Histological (osteoblast number, bone formation rate) and serum (P1NP, osteocalcin) bone formation parameters were all reduced, as were the number of osteoclasts and TRAP serum level. Differentiation of osteoblast precursors isolated from cKO versus control mice resulted in lower expression of osteoblast marker genes including Runx2, Alp, and Col1a1 on day 21, whereas the mineralization capacity was similar. Moreover, the RANKL/OPG ratio, which determines the osteoclast-supporting potential of osteoblasts, was substantially decreased by 50%. Similarly, coculturing cKO osteoblasts with control or cKO osteoclast precursors produced significantly fewer osteoclasts than coculture with control osteoblasts. Finally, exposing female mice to Epo pumps (10 U·d
-1 ) for 4 weeks resulted in trabecular bone loss (-25%) and increased osteoclast numbers (1.7-fold) in control mice only, not in cKO mice. Our data show that EpoR in osteoprogenitors is essential in regulating osteoblast function and osteoblast-mediated osteoclastogenesis via the RANKL/OPG axis. Thus, osteogenic Epo/EpoR signaling controls bone mass maintenance and contributes to Epo-induced bone loss., (© 2021. The Author(s).)- Published
- 2021
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37. Quantification of Osteoclasts in Culture, Powered by Machine Learning.
- Author
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Cohen-Karlik E, Awida Z, Bergman A, Eshed S, Nestor O, Kadashev M, Yosef SB, Saed H, Mansour Y, Globerson A, Neumann D, and Gabet Y
- Abstract
In vitro osteoclastogenesis is a central assay in bone biology to study the effect of genetic and pharmacologic cues on the differentiation of bone resorbing osteoclasts. To date, identification of TRAP+ multinucleated cells and measurements of osteoclast number and surface rely on a manual tracing requiring specially trained lab personnel. This task is tedious, time-consuming, and prone to operator bias. Here, we propose to replace this laborious manual task with a completely automatic process using algorithms developed for computer vision. To this end, we manually annotated full cultures by contouring each cell, and trained a machine learning algorithm to detect and classify cells into preosteoclast (TRAP+ cells with 1-2 nuclei), osteoclast type I (cells with more than 3 nuclei and less than 15 nuclei), and osteoclast type II (cells with more than 15 nuclei). The training usually requires thousands of annotated samples and we developed an approach to minimize this requirement. Our novel strategy was to train the algorithm by working at "patch-level" instead of on the full culture, thus amplifying by >20-fold the number of patches to train on. To assess the accuracy of our algorithm, we asked whether our model measures osteoclast number and area at least as well as any two trained human annotators. The results indicated that for osteoclast type I cells, our new model achieves a Pearson correlation (r) of 0.916 to 0.951 with human annotators in the estimation of osteoclast number, and 0.773 to 0.879 for estimating the osteoclast area. Because the correlation between 3 different trained annotators ranged between 0.948 and 0.958 for the cell count and between 0.915 and 0.936 for the area, we can conclude that our trained model is in good agreement with trained lab personnel, with a correlation that is similar to inter-annotator correlation. Automation of osteoclast culture quantification is a useful labor-saving and unbiased technique, and we suggest that a similar machine-learning approach may prove beneficial for other morphometrical analyses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cohen-Karlik, Awida, Bergman, Eshed, Nestor, Kadashev, Yosef, Saed, Mansour, Globerson, Neumann and Gabet.)
- Published
- 2021
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38. Therapeutic Potential of Vasoactive Intestinal Peptide and its Derivative Stearyl-Norleucine-VIP in Inflammation-Induced Osteolysis.
- Author
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Eger M, Liron T, Hiram-Bab S, Awida Z, Giladi E, Dangoor D, Fridkin M, Kohavi D, Gozes I, and Gabet Y
- Abstract
The common use of dental and orthopedic implants calls for special attention to the immune response leading to peri-prosthetic bone loss and implant failure. In addition to the well-established microbial etiology for oral implant failure, wear debris and in particular titanium (Ti) particles (TiP) in the implant vicinity are an important trigger of inflammation and activation of bone resorption around oral and orthopedic implants, presenting an unmet medical need. Here, we employed bacterial-derived lipopolysaccharides (LPS) to model infection and TiP to model aseptic inflammation and osteolysis. We assessed inflammation in vitro by measuring IL1β , IL6 and TNFα mRNA expression in primary macrophages, osteoclastogenesis in RANKL-induced bone marrow derived pre-osteoclasts and osteolysis in vivo in a mouse calvarial model. We also assessed the trans-epithelial penetrability and safety of the tested compound in rats. Our results show that a lipophilic super-active derivative of vasoactive intestinal peptide (VIP), namely stearyl-norleucine-VIP (SNV) presented superior anti-inflammatory and anti-osteoclastogenic effects compared to VIP in vitro . In the bacterial infection model (LPS), SNV significantly reduced IL1β expression, while VIP increased IL6 expression. In the aseptic models of osteolysis, SNV showed greater suppression of in vitro osteoclastogenesis than VIP, and significantly inhibited inflammation-induced osteolysis in vivo . We also observed that expression levels of the VIP receptor VPAC-2, but not that of VPAC-1, dramatically decreased during osteoclast differentiation. Importantly, SNV previously shown to have an increased stability compared to VIP, showed here significant trans-epithelial penetration and a clean toxicological profile, presenting a novel drug candidate that could be applied topically to counter both aseptic and infection-related bone destruction., Competing Interests: SNV is protected under a use patent application (IG, YG, DK, ME) and under term-sheet for commercialization (Ramot at Tel Aviv University, Light Ventures and Osteop)., (Copyright © 2021 Eger, Liron, Hiram-Bab, Awida, Giladi, Dangoor, Fridkin, Kohavi, Gozes and Gabet.)
- Published
- 2021
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39. Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis.
- Author
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Baraghithy S, Soae Y, Assaf D, Hinden L, Udi S, Drori A, Gabet Y, and Tam J
- Subjects
- Animals, Cannabinoids pharmacology, Diabetic Nephropathies, Glucose pharmacology, Homeostasis drug effects, Homeostasis physiology, Humans, Kidney drug effects, Kidney metabolism, Kidney Tubules, Proximal metabolism, Male, Mice, Inbred C57BL, Mice, Blood Glucose metabolism, Bone Remodeling physiology, Kidney Tubules, Proximal drug effects, Osteoporosis metabolism
- Abstract
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB
1 R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1 R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1 R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1 R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.- Published
- 2021
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40. Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice.
- Author
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Kolomansky A, Kaye I, Ben-Califa N, Gorodov A, Awida Z, Sadovnic O, Ibrahim M, Liron T, Hiram-Bab S, Oster HS, Sarid N, Perry C, Gabet Y, Mittelman M, and Neumann D
- Subjects
- Adult, Aged, Animals, Cross-Sectional Studies, Female, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Positron Emission Tomography Computed Tomography, Retrospective Studies, Treatment Outcome, Antigens, CD20 immunology, Antineoplastic Agents, Immunological administration & dosage, B-Lymphocytes immunology, Bone Density drug effects, Bone Resorption therapy, Immunotherapy methods, Lymphocyte Depletion, Lymphoma, Follicular therapy, Rituximab administration & dosage
- Abstract
Immunotherapy with anti-CD20-specific antibodies (rituximab), has become the standard of care for B cell lymphoproliferative disorders and many autoimmune diseases. In rheumatological patients the effect of rituximab on bone mass yielded conflicting results, while in lymphoma patients it has not yet been described. Here, we used cross-sectional X-ray imaging (CT/PET-CT) to serially assess bone density in patients with follicular lymphoma receiving rituximab maintenance therapy. Remarkably, this treatment prevented the decline in bone mass observed in the control group of patients who did not receive active maintenance therapy. In accordance with these data, anti-CD20-mediated B cell depletion in normal C57BL/6J female mice led to a significant increase in bone mass, as reflected by a 7.7% increase in bone mineral density (whole femur), and a ~5% increase in cortical as well as trabecular tissue mineral density. Administration of anti-CD20 antibodies resulted in a significant decrease in osteoclastogenic signals, including RANKL, which correlated with a reduction in osteoclastogenic potential of bone marrow cells derived from B-cell-depleted animals. Taken together, our data suggest that in addition to its anti-tumor activity, anti-CD20 treatment has a favorable effect on bone mass. Our murine studies indicate that B cell depletion has a direct effect on bone remodeling., (Copyright © 2020 Kolomansky, Kaye, Ben-Califa, Gorodov, Awida, Sadovnic, Ibrahim, Liron, Hiram-Bab, Oster, Sarid, Perry, Gabet, Mittelman and Neumann.)
- Published
- 2020
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41. Author Correction: Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.
- Author
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Eger M, Bader M, Bree D, Hadar R, Nemirovski A, Tam J, Levy D, Pick CG, and Gabet Y
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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42. The Cannabinoids Effect on Bone Formation and Bone Healing.
- Author
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Raphael-Mizrahi B and Gabet Y
- Subjects
- Animals, Endocannabinoids metabolism, Fracture Healing physiology, Humans, Mice, Osteogenesis physiology, Rats, Sex Factors, Cannabidiol pharmacology, Cannabinoids pharmacology, Fracture Healing drug effects, Osteogenesis drug effects, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 metabolism
- Abstract
Purpose of Review: Here, we overview the latest findings from studies investigating the skeletal endocannabinoid (EC) system and its involvement in bone formation and resorption., Recent Findings: The endocannabinoid system consists of endogenous ligands, receptors, and enzymes. The main cannabinoids found in the cannabis plant are Δ
9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoid receptors CB1 and CB2 are expressed in bone and regulate bone homeostasis in rodents and humans. CBD treatment was shown to enhance fracture healing in rats. Recent studies in mice indicate that strain, age, and sex differences dictate the skeletal outcome of the EC activation. CBD treatment was shown to enhance bone healing, but needs validation in clinical trials. While research shows that EC activity protects against bone loss, studies on CB1 and CB2 agonists in bone regeneration models are lacking. Whether modulating the EC system would affect bone repair remains therefore an open question worth investigating.- Published
- 2020
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43. Cartilage -specific knockout of Sirt1 significantly reduces bone quality and catch-up growth efficiency.
- Author
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Shtaif B, Bar-Maisels M, Gabet Y, Hiram-Bab S, Yackobovitch-Gavan M, Phillip M, and Gat-Yablonski G
- Subjects
- Animals, Cartilage, Chondrocytes, Mice, Mice, Knockout, Bone Development, Bone and Bones, Growth Plate, Sirtuin 1 genetics
- Abstract
Background: Spontaneous catch-up (CU) growth occurs when a growth-restricting factor is resolved. However, its efficiency is sometimes inadequate and growth deficits remain permanent. The therapeutic toolbox for short stature is currently very limited, thus, finding new regulatory pathways is important for the development of novel means of treatment. Our previous studies using a nutrition-induced CU growth model showed that the level of sirtuin-1 (Sirt1) was significantly increased in food-restricted animals and decreased during CU growth., Aim: This study sought to investigate the role of Sirt1 in modulating the response of the epiphyseal growth plate (EGP) to nutritional manipulation., Method: Collagen type II-specific Sirt1 knockout (CKO) mice were tested for response to our CU growth model consisting of a period of food restriction followed by re-feeding., Results: The transgenic CKO mice weighed more than the control (CTL) mice, their EGP was higher and less organized, specifically at the resting and proliferative zones, leading to shorter bones. Ablation of Sirt1 in the chondrocytes was found to have a dramatic effect on bone mineralization on micro-CT analysis. The CKO mice were less responsive to the nutritional manipulation, and their CU growth was less efficient. They remained shorter than the CTL mice who corrected the food restriction-induced growth deficit during the re-feeding period., Conclusions: Sirt1 appears to be important for normal regulation of the EGP. In its absence, the EGP is less organized and CU growth is less efficient. These results suggest that SIRT1 may serve as a novel therapeutic target for short stature., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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44. Erythropoietin receptor in B cells plays a role in bone remodeling in mice.
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Deshet-Unger N, Kolomansky A, Ben-Califa N, Hiram-Bab S, Gilboa D, Liron T, Ibrahim M, Awida Z, Gorodov A, Oster HS, Mittelman M, Rauner M, Wielockx B, Gabet Y, and Neumann D
- Subjects
- Animals, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Cell Transdifferentiation drug effects, Female, Gene Knockout Techniques, Mice, Osteogenesis, RANK Ligand metabolism, Receptors, Erythropoietin metabolism, B-Lymphocytes cytology, Bone Remodeling drug effects, Erythropoietin pharmacology, Receptors, Erythropoietin genetics
- Abstract
Erythropoietin (EPO) is a key regulator of erythropoiesis. However, EPO receptors (EPO-Rs) are also expressed on non-erythroid cell types, including myeloid and bone cells. Immune cells also participate in bone homeostasis. B cells produce receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG), two pivotal regulators of bone metabolism. Here we explored the ability of B cells to transdifferentiate into functional osteoclasts and examined the role of EPO in this process in a murine model. Methods: We have combined specifically-designed experimental mouse models and in vitro based osteoclastogenesis assays, as well as PCR analysis of gene expression. Results: (i) EPO treatment in vivo increased RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occured in vivo and in vitro, as demonstrated by B cell lineage tracing in murine models; (iii) B-cell-derived osteoclastogenesis in vitro was restricted to Pro-B cells expressing CD115/CSF1-R and is enhanced by EPO; (iv) EPO treatment increased the number of B-cell-derived preosteoclasts (β3
+ CD115+ ), suggesting a physiological rationale for B cell derived osteoclastogenesis; (v) finally, mice with conditional EPO-R knockdown in the B cell lineage (cKD) displayed a higher cortical and trabecular bone mass. Moreover, cKD displayed attenuated EPO-driven trabecular bone loss, an effect that was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling and suggests their involvement in the regulation of bone homeostasis and possibly in EPO-stimulated erythropoietic response. Importantly, we present here for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo ., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)- Published
- 2020
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45. Erythropoietin Mediated Bone Loss in Mice Is Dose-Dependent and Mostly Irreversible.
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Kolomansky A, Hiram-Bab S, Ben-Califa N, Liron T, Deshet-Unger N, Mittelman M, Oster HS, Rauner M, Wielockx B, Neumann D, and Gabet Y
- Subjects
- Animals, Bone Resorption diagnostic imaging, Bone Resorption pathology, Cancellous Bone diagnostic imaging, Cancellous Bone drug effects, Cells, Cultured, Erythropoietin administration & dosage, Erythropoietin pharmacology, Female, Femur diagnostic imaging, Femur drug effects, Hemoglobins metabolism, Mice, Mice, Inbred C57BL, Spine diagnostic imaging, Spine drug effects, Bone Resorption etiology, Erythropoietin adverse effects
- Abstract
Recent studies have demonstrated that erythropoietin (EPO) treatment in mice results in trabecular bone loss. Here, we investigated the dose-response relationship between EPO, hemoglobin (Hgb) and bone loss and examined the reversibility of EPO-induced damage. Increasing doses of EPO over two weeks led to a dose-dependent increase in Hgb in young female mice, accompanied by a disproportionate decrease in trabecular bone mass measured by micro-CT (µCT). Namely, increasing EPO from 24 to 540 IU/week produced a modest 12% rise in Hgb (20.2 ± 1.3 mg/dL vs 22.7 ± 1.3 mg/dL), while trabecular bone volume fraction (BV/TV) in the distal femur decreased dramatically (27 ± 8.5% vs 53 ± 10.2% bone loss). To explore the long-term skeletal effects of EPO, we treated mice for two weeks (540 IU/week) and monitored bone mass changes after treatment cessation. Six weeks post-treatment, there was only a partial recovery of the trabecular microarchitecture in the femur and vertebra. EPO-induced bone loss is therefore dose-dependent and mostly irreversible at doses that offer only a minor advantage in the treatment of anemia. Because patients requiring EPO therapy are often prone to osteoporosis, our data advocate for using the lowest effective EPO dose for the shortest period of time to decrease thromboembolic complications and minimize the adverse skeletal outcome.
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- 2020
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46. A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis.
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Levy R, Levet C, Cohen K, Freeman M, Mott R, Iraqi F, and Gabet Y
- Subjects
- Animals, Computer Simulation, Female, Fractures, Bone genetics, Genotype, Homeostasis, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Quantitative Trait Loci, RNA-Seq, X-Ray Microtomography, Bone Density, Carrier Proteins genetics, Genome-Wide Association Study, Osteoporosis genetics
- Abstract
Low bone mass and an increased risk of fracture are predictors of osteoporosis. Individuals who share the same bone-mineral density (BMD) vary in their fracture risk, suggesting that microstructural architecture is an important determinant of skeletal strength. Here, we utilized the rich diversity of the Collaborative Cross mice to identify putative causal genes that contribute to the risk of fractures. Using microcomputed tomography, we examined key structural features that pertain to bone quality in the femoral cortical and trabecular compartments of male and female mice. We estimated the broad-sense heritability to be 50-60% for all examined traits, and we identified five quantitative trait loci (QTL) significantly associated with six traits. We refined each QTL by combining information inferred from the ancestry of the mice, ranging from RNA-Seq data and published literature to shortlist candidate genes. We found strong evidence for new candidate genes, particularly Rhbdf2, whose close association with the trabecular bone volume fraction and number was strongly suggested by our analyses. We confirmed our findings with mRNA expression assays of Rhbdf2 in extreme-phenotype mice, and by phenotyping bones of Rhbdf2 knockout mice. Our results indicate that Rhbdf2 plays a decisive role in bone mass accrual and microarchitecture.
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- 2020
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47. Hormone-Independent Sexual Dimorphism in the Regulation of Bone Resorption by Krox20.
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Sabag E, Halperin E, Liron T, Hiram-Bab S, Frenkel B, and Gabet Y
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- Animals, Apoptosis drug effects, Cell Differentiation drug effects, Cell Lineage, Cell Proliferation drug effects, Early Growth Response Protein 2 deficiency, Early Growth Response Protein 2 genetics, Female, Gene Expression Regulation drug effects, Haploinsufficiency genetics, Male, Mice, Knockout, Monocytes metabolism, Osteoclasts drug effects, Phenotype, Bone Resorption metabolism, Bone Resorption pathology, Early Growth Response Protein 2 metabolism, Gonadal Steroid Hormones metabolism, Sex Characteristics
- Abstract
Krox20/EGR2 is a zinc finger transcription factor, implicated in the development of the hindbrain, nerve myelination, and tumor suppression. In skeletal biology, we have demonstrated that Krox20 also regulates adult bone metabolism. We and others have characterized several functions of Krox20 in the osteoclast lineage, namely, preosteoclast proliferation and differentiation, and mature osteoclast apoptosis. We have previously reported that systemically Krox20-haploinsufficient mice have a low bone mass with increased bone resorption. However, new data have now revealed that this phenotype is restricted to females. In addition, we discovered that conditional knockout of Krox20 (cKO) restricted to osteoclast progenitors is sufficient to induce the same female-specific bone loss observed in systemic mutants. To test whether this sexual dimorphism results from an interaction between Krox20 and sex hormones, we examined the sex- and hormone-dependent role of Krox20 deficiency on proliferation and apoptosis in osteoclastic cells. Our results indicate that male and female sex hormones (dihydrotestosterone [DHT] and estradiol [E2], respectively) as well as Krox20 inhibit preosteoclast proliferation and augment osteoclast apoptosis. The observation that Krox20 expression is inhibited by DHT and E2 negates the hypothesis that the effect of sex hormones is mediated by an increase in Krox20 expression. Interestingly, the effect of Krox20 deficiency was observed only with cells derived from female animals, regardless of any sex hormones added in vitro. In addition, we have identified sexual dimorphism in the expression of several Krox20-related genes, including NAB2. This sex-specific epigenetic profile was established at puberty, maintained in the absence of sex hormones, and explains the female-specific skeletal importance of Krox20. The findings described in this study emphasize the medical importance of sex differences, which may be determined at the epigenetic level. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)
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- 2019
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48. Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.
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Eger M, Bader M, Bree D, Hadar R, Nemirovski A, Tam J, Levy D, Pick CG, and Gabet Y
- Subjects
- Animals, Arachidonic Acids metabolism, Brain Injuries, Traumatic pathology, Endocannabinoids metabolism, Glycerides metabolism, Male, Mast Cells, Mice, Mice, Inbred ICR, Mice, Knockout, Polyunsaturated Alkamides metabolism, Rimonabant pharmacology, Skull pathology, Brain Injuries, Traumatic metabolism, Receptor, Cannabinoid, CB1 metabolism, Skull metabolism
- Abstract
Brain trauma was clinically associated with increased osteogenesis in the appendicular skeleton. We showed previously in C57BL/6J mice that mild traumatic brain injury (mTBI) transiently induced bone formation in the femur via the cannabinoid-1 (CB1) receptor. Here, we subjected ICR mice to mTBI and examined the bone response in the skull using microCT. We also measured mast cell degranulation (MCD)72 h post-injury. Finally, we measured brain and calvarial endocannabinoids levels post-mTBI. mTBI led to decreased bone porosity on the contralateral (untouched) side. This effect was apparent both in young and mature mice. Administration of rimonabant (CB1 inverse agonist) completely abrogated the effect of mTBI on calvarial porosity and significantly reduced MCD, compared with vehicle-treated controls. We also found that mTBI resulted in elevated levels of anandamide, but not 2-arachidonoylglycerol, in the contralateral calvarial bone, whereas brain levels remained unchanged. In C57BL/6J CB1 knockout mice, mTBI did not reduce porosity but in general the porosity was significantly lower than in WT controls. Our findings suggest that mTBI induces a strain-specific CB1-dependent bone anabolic response in the skull, probably mediated by anandamide, but seemingly unrelated to inflammation. The endocannabinoid system is therefore a plausible target in management of bone response following head trauma.
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- 2019
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49. Functional effects of synthetic cannabinoids versus Δ 9 -THC in mice on body temperature, nociceptive threshold, anxiety, cognition, locomotor/exploratory parameters and depression.
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Schreiber S, Bader M, Lenchinski T, Meningher I, Rubovitch V, Katz Y, Cohen E, Gabet Y, Rotenberg M, Wolf EU, and Pick CG
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- Animals, Anxiety physiopathology, Body Temperature drug effects, Depression physiopathology, Male, Maze Learning drug effects, Memory drug effects, Mice, Inbred ICR, Motor Activity drug effects, Nociception drug effects, Sensory Thresholds drug effects, Valine pharmacology, Dronabinol pharmacology, Indazoles pharmacology, Psychotropic Drugs pharmacology, Valine analogs & derivatives
- Abstract
Synthetic cannabinoids are psychoactive substances designed to mimic the euphorigenic effects of the natural cannabis. Novel unregulated compounds appear once older compounds become illegal. It has been previously reported that synthetic cannabinoids are different than Δ
9 -tetrahydrocannabinol (Δ9 -THC) as they have chemical structures unrelated to Δ9 -THC, different metabolism and, often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Δ9 -THC on body temperature, nociceptive threshold, anxiety, memory function, locomotor and exploratory parameters, and depression. We performed a battery of behavioural and motor tests starting 50 minutes post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHMINACA and PB-22. All synthetic cannabinoids and Δ9 -THC caused hypothermia, but only Δ9 -THC induced a clear antinociceptive effect. All synthetic cannabinoids and Δ9 -THC caused decreased anxiety levels, spatial memory deficits and decreased exploratory behaviour as measured in the elevated plus maze, Y-maze and staircase paradigm, respectively. However, all synthetic cannabinoids but not Δ9 -THC demonstrated decreased locomotor activity in the staircase test. Moreover, only AB-FUBINACA and Δ9 -THC affected the gait balance and grip strength of the mice as was assessed by the latency time to fall from a rod. In the forced swimming test, PB-22 caused elevated depression-like behaviour while AB-FUBINACA induced a reversed effect. These results suggest varied effects among different synthetic cannabinoids and Δ9 -THC. Further studies are needed to characterize the overall effects and differences between these synthetic cannabinoids and Δ9 -THC., (© 2018 Society for the Study of Addiction.)- Published
- 2019
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50. Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity.
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Baraghithy S, Smoum R, Drori A, Hadar R, Gammal A, Hirsch S, Attar-Namdar M, Nemirovski A, Gabet Y, Langer Y, Pollak Y, Schaaf CP, Rech ME, Gross-Tsur V, Bab I, Mechoulam R, and Tam J
- Subjects
- Animals, Bone Density drug effects, Bone Density genetics, Humans, Mice, Mice, Knockout, Osteoblasts metabolism, Osteoblasts pathology, Osteoclasts metabolism, Osteoclasts pathology, Serine pharmacology, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Bone Remodeling drug effects, Bone Remodeling genetics, Osteogenesis drug effects, Osteogenesis genetics, Prader-Willi Syndrome genetics, Prader-Willi Syndrome metabolism, Prader-Willi Syndrome pathology, Proteins genetics, Proteins metabolism, Serine metabolism
- Abstract
Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2
-/- mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2-/- mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)- Published
- 2019
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