The regulation of E3 ubiquitin ligases Cbl and its cross talking in bone homeostasis

2020 ◽  
Vol 15 ◽  
Author(s):  
Xiaobin Yang ◽  
Dingjun Hao ◽  
Baorong He
Keyword(s):  
Cellular Proliferation ◽  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Bone Homeostasis ◽  
And Migration ◽  
First Time ◽  
Definite Role

: The E3 ubiquitin ligases Cbl has been found play an important role in regulating cellular proliferation and migration. Whereas the excessive differentiation of osteoclast and/or its over expressing of resorptive functions could lead the pathological bone homeostasis by overly bone matrix degradation. Since the first time of the important role of Cbl in the regulating osteoclast differentiation (also named osteoclastogenesis) has been reported in decades ago. The extensively studies have been conducted for in-depth exploring the Cbl’s definite role during osteoclastogenesis, as well as its cross talking with other signaling pathways (such as: Src and PI3K signaling) in bone homeostasis. Herein, our current study aim to briefly conclude the current studies of osteoclastogenesis and the regulatory role of Cbl, as well as its cross-talking in bone homeostasis.

scholarly journals FRI0376 EFFECT OF CARBAMYLATED LOW-DENSITY LIPOPROTEINS ON BONE CELLS HOMEOSTASIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 784.2-785
Author(s):  
B. Lucchino ◽  
M. Leopizzi ◽  
T. Colasanti ◽  
V. DI Maio ◽  
C. Alessandri ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Low Density Lipoproteins ◽  
Tartrate Resistant Acid Phosphatase ◽  
Low Density ◽  
Bone Homeostasis ◽  
Research Support ◽  
Erosive Disease

Background:Carbamylation is a post-translational modification occurring under several conditions such as uremia, smoking and chronic inflammation as in rheumatoid arthritis (RA). Low-density lipoproteins (LDL) represent a target of carbamylation. Carbamylated-LDL (cLDL) have an increased inflammatory and atherogenic potential. Growing evidence supports an influence of modified lipids on bone cells homeostasis. However, the role of cLDL on bone cells physiology is still unknown.Objectives:Considering the rate of carbamylation and the role of anti-carbamylated proteins antibodies as markers of erosive disease in RA, the purpose of this study is to investigate the effect of cLDL on bone homeostasis.Methods:In-vitrocarbamylation of LDL was performed as previously described by Ok et al. (Kidney Int. 2005). Briefly, native LDL (nLDL) were treated with potassium cyanate (KOCN) for 4 hours, followed by excessive dialysis for 36 hours to remove KOCN. Both osteoclasts (OCs) and osteoblasts (OBLs) were treated at baseline with 20 μg/ml, 100 μg/ml and 200 μg/ml of cLDL or nLDL. To induce osteoclast differentiation, CD14+ monocytes were isolated from peripheral blood of healthy donors by magnetic microbeads separation and then cultured on a 96-wells plate in DMEM media supplemented with RANKL and M-CSF. After 10 days cells were fixed, stained for tartrate-resistant acid phosphatase (TRAP), a marker of OC differentiation, and counted. OBLs were isolated from bone specimens of 3 patients who had undergone to knee or hip arthroplasty for osteoarthritis and treated for 5 days with different concentrations of cLDL and nLDL. OBLs were fixed and stained for alkaline phosphatase positive activity (ALP), a marker of osteogenic differentiation. Total RNA was extracted from cell lysates. Copies of single-stranded complementary DNA (cDNA) were synthesized and analyzed by real-time PCR to evaluate RANKL and Osteoprotegerin (OPG) mRNA expression levels.Results:In OCLs culture, cLDL significantly decreased the number of OC compared to untreated cells (200 μg/ml p=0,0015) and nLDL treated cells (200 μg/ml p= 0,011; 20 μg/ml p= 0,0014) (Fig 1). Moreover, treatment with cLDL induced an increase of not terminally differentiated OCs, reduced dimensions of OCs, less intense TRAP staining and vacuolization (Fig 2). In OBLs culture, cLDL (20, 100 μg/ml) significantly reduced the ALP activity of OBLs compared with untreated cells (p<0.05) (Fig 3). nLDL did not affect the ALP expression. Treatment with cLDL stimulated RANKL mRNA expression in osteoblasts increasing the RANKL/OPG ratio (Fig 4).Fig 1.Fig 2.Fig 3.Fig 4.Conclusion:cLDL induce a significant depression of OC and OBL differentiation. Moreover, cLDL increase RANKL expression in OBL, unbalancing bone tissue turnover towards bone resorption. Accordingly, cLDL could be implicated in the bone loss characterizing several conditions associated to an increased carbamylation, such as RADisclosure of Interests:Bruno Lucchino: None declared, Martina Leopizzi: None declared, Tania Colasanti: None declared, Valeria Di Maio: None declared, cristiano alessandri Grant/research support from: Pfizer, Guido Valesini: None declared, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi, Manuela Di Franco: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Consultant of: Novartis, Gilead, Lilly, Sanofi, Celgene, Speakers bureau: Lilly

scholarly journals Inhibitory Effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside on RANKL-Induced Osteoclast Differentiation and ROS Generation in Macrophages

2020 ◽  
Vol 22 (1) ◽  
pp. 222
Author(s):  
Eun-Nam Kim ◽  
Ga-Ram Kim ◽  
Jae Sik Yu ◽  
Ki Hyun Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Disease ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Bone Diseases ◽  
Ros Generation ◽  
Bone Homeostasis ◽  
Disease Treatment ◽  
And Migration

In bone homeostasis, bone loss due to excessive osteoclasts and inflammation or osteolysis in the bone formation process cause bone diseases such as osteoporosis. Suppressing the accompanying oxidative stress such as ROS in this process is an important treatment strategy for bone disease. Therefore, in this study, the effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (BAG), an arylbutanoid glycoside isolated from Betula platyphylla var. japonica was investigated in RANKL-induced RAW264.7 cells and LPS-stimulated MC3E3-T1 cells. BAG inhibited the activity of TRAP, an important marker of osteoclast differentiation and F-actin ring formation, which has osteospecific structure. In addition, the protein and gene levels were suppressed of integrin β3 and CCL4, which play an important role in the osteoclast-induced bone resorption and migration of osteoclasts, and inhibited the production of ROS and restored the expression of antioxidant enzymes such as SOD and CAT lost by RANKL. The inhibitory effect of BAG on osteoclast differentiation and ROS production appears to be due to the inhibition of MAPKs phosphorylation and NF-κβ translocation, which play a major role in osteoclast differentiation. In addition, BAG inhibited ROS generated by LPS and effectively restores the mineralization of lost osteoblasts, thereby showing the effect of bone formation in the inflammatory situation accompanying bone loss by excessive osteoclasts, suggesting its potential as a new natural product-derived bone disease treatment.

Abstract 2178: Sonic Hedgehog In Adult Hypoxic Cerebellum

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Giuseppe Straface ◽  
Andrea Flex ◽  
Federico Biscetti ◽  
Eleonora Gaetani ◽  
Giovanni Pecorini ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Target Genes ◽  
Positive Staining ◽  
Lacz Gene ◽  
Downstream Target ◽  
Shh Pathway ◽  
And Migration ◽  
First Time ◽  
Proliferation And Migration

Background: Cerebellar hypoxia is responsible for important aspects of cognitive deterioration and motor disturbances in neurological disorders, such as stroke, vascular dementia, and neurodegeneration. In the cerebellum, VEGF is significantly upregulated after hypoxia and is able to induce angiogenesis, reduce neuronal apoptosis, and regulate neuronal differentiation, proliferation, and migration. But, VEGF is not sufficient to provide neuroprotection. A crucial role is played by growth associated protein-43 (GAP43), for which important activities have been described. The purpose of this study was to investigate the role of the developmental Sonic hedgehog (Shh) signaling pathway in postnatal hypoxic cerebellum and its relationship with VEGF and GAP43 expression. Methods: We used adult C57BL/6J mice, ptc1-lacZ mice, and GAP43−/− mice for these experiments. Ptc1-lacZ mice carry a non-disruptive insertion of the lacZ gene under the control of the ptc1 promoter. Ptc1 is a downstream-transcriptional target of Shh and its upregulation indicates activation of the Shh pathway. Mice were exposed to systemic normobaric hypoxia (6%O 2 ) for 6 hours and the expression of Shh, Ptc1, VEGF, and GAP43 were investigated. Results: After exposure to hypoxia, Shh-positive staining was detected in Purkinje cells (PCs). The same cells were also lacZ(ptc1)-positive, indicating that PCs are both Shh-producing and -responding elements. Also the cells of the internal granular layer (IGL) were lacZ(ptc1)-positive, indicating that these cells are Shh-responsive. LacZ(ptc1)-positive IGL cells were also immunopositive for VEGF and GAP-43. We also found that ptc1 expression is lost in PCs of GAP43−/− mice, indicating that Shh requires GAP43 to activate its downstream target genes in PCs. Finally, when cultures enriched in granular cells were stimulated with Shh recombinant protein, GAP43 phosphorylation was increased. This effect was inhibited by Shh-inhibitor cyclopamine. Conclusions: This is the first time that hypoxia is reported to activate the Shh pathway in the adult. Our data suggest that the Shh pathway might be important for the cerebellar response to hypoxia, through interactions with VEGF and GAP43.

scholarly journals PIP5k1β controls bone homeostasis through modulating both osteoclast and osteoblast differentiation

2019 ◽  
Vol 12 (1) ◽  
pp. 55-70 ◽  
Author(s):  
Xiaoying Zhao ◽  
Penglei Cui ◽  
Guoli Hu ◽  
Chuandong Wang ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Nuclear Translocation ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Osteoporosis Prevention ◽  
Cytoskeletal Organization ◽  
Fos Expression ◽  
And Migration ◽  
And Function ◽  
Proliferation And Migration

Abstract PIP5k1β is crucial to the generation of phosphotidylinosotol (4, 5)P2. PIP5k1β participates in numerous cellular activities, such as B cell and platelet activation, cell phagocytosis and endocytosis, cell apoptosis, and cytoskeletal organization. In the present work, we aimed to examine the function of PIP5k1β in osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment. We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and that PIP5k1β was highly expressed during both osteoclast and osteoblast differentiation. Deletion of the gene was found to enhance the proliferation and migration of bone marrow-derived macrophage-like cells to promote osteoclast differentiation. PIP5k1β−/− osteoclasts exhibited normal cytoskeleton architecture but stronger resorption activity. PIP5k1β deficiency also promoted activation of mitogen-activated kinase and Akt signaling, enhanced TRAF6 and c-Fos expression, facilitated the expression and nuclear translocation of NFATC1, and upregulated Grb2 expression, thereby accelerating osteoclast differentiation and function. Finally, PIP5k1β enhanced osteoblast differentiation by upregulating master gene expression through triggering smad1/5/8 signaling. Therefore, PIP5k1β modulates bone homeostasis and remodeling.

scholarly journals The skeleton: a multi-functional complex organ. The role of key signalling pathways in osteoclast differentiation and in bone resorption

2011 ◽  
Vol 211 (2) ◽  
pp. 131-143 ◽  
Author(s):  
David J Mellis ◽  
Cecile Itzstein ◽  
Miep H Helfrich ◽  
Julie C Crockett
Keyword(s):  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Signalling Pathways ◽  
Monogenic Diseases ◽  
Formation Function ◽  
Functional Complex ◽  
And Function ◽  
Cytoskeletal Rearrangements

Osteoclasts are the specialised cells that resorb bone matrix and are important both for the growth and shaping of bones throughout development as well as during the process of bone remodelling that occurs throughout life to maintain a healthy skeleton. Osteoclast formation, function and survival are tightly regulated by a network of signalling pathways, many of which have been identified through the study of rare monogenic diseases, knockout mouse models and animal strains carrying naturally occurring mutations in key molecules. In this review, we describe the processes of osteoclast formation, activation and function and discuss the major transcription factors and signalling pathways (including those that control the cytoskeletal rearrangements) that are important at each stage.

scholarly journals Skin Regenerative Potential of Cupuaçu Seed Extract (Theobroma grandiflorum), a Native Fruit from the Amazon: Development of a Topical Formulation Based on Chitosan-Coated Nanocapsules

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 207
Author(s):  
Geisa Nascimento Barbalho ◽  
Breno Noronha Matos ◽  
Gabriel Ferreira da Silva Brito ◽  
Thamires da Cunha Miranda ◽  
Thuany Alencar-Silva ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Seed Extract ◽  
Skin Regeneration ◽  
Topical Formulation ◽  
Biotechnological Potential ◽  
Theobroma Grandiflorum ◽  
Hyaluronic Acid Synthase ◽  
Low Molecular Weight Chitosan ◽  
And Migration ◽  
First Time

Scarless skin regeneration is a challenge in regenerative medicine. Herein, we explore the regenerative potential of a Cupuaçu seed extract (Theobroma grandiflorum) to develop an innovative skin regeneration formulation based on chitosan-coated nanocapsules. Cupuaçu seed extract significantly stimulated cell proliferation and migration. A reparative gene expression profile could be verified following extract treatment, which included high levels of MKI67, a cellular proliferation marker, and extracellular matrix genes, such as ELN and HAS2, which code for elastin and hyaluronic acid synthase 2. Formulations with Cupuaçu seed extract successfully entrapped into nanocapsules (EE% > 94%) were developed. Uncoated or coated nanocapsules with low-molecular-weight chitosan presented unimodal size distribution with hydrodynamic diameters of 278.3 ± 5.0 nm (PDI = 0.18 ± 0.02) and 337.2 ± 2.1 nm (PDI = 0.27 ± 0.01), respectively. Both nanosystems were physically stable for at least 120 days and showed to be non-irritating to reconstructed human epidermis. Chitosan coating promoted active penetration into undamaged skin areas, which were still covered by the stratum corneum. In conclusion, the present study demonstrated for the first time the biotechnological potential of the frequently discarded Cupuaçu seed as a valuable pharmaceutical ingredient to be used in regenerative skin products.

scholarly journals PIP5k1 β controls bone homeostasis through modulating both osteoclast and osteoblast differentiation

2018 ◽  
Author(s):  
Xiaoying Zhao ◽  
Guoli Hu ◽  
Chuandong Wang ◽  
Lei Jiang ◽  
Jingyu Zhao ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Nuclear Translocation ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Osteoporosis Prevention ◽  
Genes Expression ◽  
And Migration ◽  
And Function ◽  
Insight Into ◽  
Proliferation And Migration

AbstractPIP5K1β is crucial to generation of phosphotidylinosotol (4, 5) P2. PIP5K1β participates in numerous cellular activities, such as B cell and platelet activation, cell phagocytosis and endocytosis, cell apoptosis, and cytoskeletal organization. In the present work, we aimed to make insight into the function of PIP5K1β in osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment. We discovered that PIP5k1β deletion in mice resulted in obvious bone loss and PIP5K1β was highly expressed both during osteoclast and osteoblast differentiation, besides, PIP5K1β deletion enhanced the proliferation and migration of BMMs to promote osteoclast differentiation. PIP5k1β−/− osteoclast exhibited normal cytoskeleton architecture but stronger resorption activity. PIP5k1β deficiency also promoted activation of MAPK and Akt signaling, enhanced TRAF6 and c-Fos expression, facilitated the expression and nuclear translocation of NFATC1 and upregulated Grb2 expression, thereby accelerating osteoclast differentiation and function. Finally, PIP5K1β enhanced osteoblast differentiation by upregulating master genes expression through triggering smad1/5/8 signaling. Thereby, PIP5K1β modulate bone homeostasis and remodeling.

The effects of oxidative stress on the development of atherosclerosis

2019 ◽  
Vol 400 (6) ◽  
pp. 711-732 ◽  
Author(s):  
Mohsen Khosravi ◽  
Adeleh Poursaleh ◽  
Ghasem Ghasempour ◽  
Shaikhnia Farhad ◽  
Mohammad Najafi
Keyword(s):  
Oxidative Stress ◽  
Cellular Proliferation ◽  
Nadh Oxidase ◽  
Macrophage Polarization ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Oxidative Modification ◽  
Oxidative Enzymes ◽  
Matrix Remodeling ◽  
And Migration

Abstract Atherosclerosis is a cardiovascular disease (CVD) known widely world wide. Several hypothesizes are suggested to be involved in the narrowing of arteries during process of atherogenesis. The oxidative modification hypothesis is related to oxidative and anti-oxidative imbalance and is the most investigated. The aim of this study was to review the role of oxidative stress in atherosclerosis. Furthermore, it describes the roles of oxidative/anti-oxidative enzymes and compounds in the macromolecular and lipoprotein modifications and in triggering inflammatory events. The reactive oxygen (ROS) and reactive nitrogen species (RNS) are the most important endogenous sources produced by non-enzymatic and enzymatic [myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADH) oxidase and lipoxygenase (LO)] reactions that may be balanced with anti-oxidative compounds [glutathione (GSH), polyphenols and vitamins] and enzymes [glutathione peroxidase (Gpx), peroxiredoxins (Prdx), superoxide dismutase (SOD) and paraoxonase (PON)]. However, the oxidative and anti-oxidative imbalance causes the involvement of cellular proliferation and migration signaling pathways and macrophage polarization leads to the formation of atherogenic plaques. On the other hand, the immune occurrences and the changes in extra cellular matrix remodeling can develop atherosclerosis process.

FBXW10 promotes hepatocarcinogenesis in male patients and mice

2019 ◽  
Vol 41 (5) ◽  
pp. 689-698 ◽  
Author(s):  
Yuan-Deng Luo ◽  
Jie Zhang ◽  
Lei Fang ◽  
Yan-Yin Zhu ◽  
Yue-Mei You ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Independent Risk Factor ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Poor Survival ◽  
Male Patients ◽  
And Migration ◽  
F Box Protein ◽  
Proliferation And Migration

Abstract Hepatocellular carcinoma (HCC) is reported to associate with abnormal expression of SCF E3 ubiquitin ligases. FBXW10, an F-box protein of the E3 ubiquitin ligases, was abnormally regulated in HCC patients. However, whether FBXW10 is associated with HCC has not yet been evaluated. Here, we analyzed the associations between overall survival and various risk factors in 191 HCC tissues. Univariate and multivariate analyses demonstrated that FBXW10 was an independent risk factor related to HCC prognosis. The results showed that FBXW10, gender and tumor state were strongly associated with overall survival in HCC patients. Furthermore, high expression of FBXW10 was associated with poor survival among male HCC patients but not female HCC patients. FBXW10 was more highly expressed in male HCC tissues and more strongly related to vascular invasion in male HCC patients. Consistent with these findings, the male FBXW10-Tg(+) mice were more susceptible to tumorigenesis, changes in regenerative capacity, and liver injury and inflammation but not changes in liver function than FBXW10-Tg(–) mice. FBXW10 promoted cell proliferation and migration in HCC cell lines. Our findings reveal that FBXW10, an independent risk factor for HCC, promotes hepatocarcinogenesis in male patients, and is also a potential prognostic marker in male patients with HCC.

scholarly journals Toward Understanding the Role of Amot80 Lipid Binding in Cellular Proliferation and Migration

2014 ◽  
Vol 106 (2) ◽  
pp. 303a
Author(s):  
Emily L. Donovan ◽  
Ann C. Kimble-Hill ◽  
Thomas D. Hurley ◽  
Clark D. Wells
Keyword(s):  
Cellular Proliferation ◽  
Lipid Binding ◽  
And Migration ◽  
Proliferation And Migration
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