scholarly journals Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Xiaoxiao Li ◽  
Wei Wei ◽  
HoangDinh Huynh ◽  
Hao Zuo ◽  
Xueqian Wang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Feedback Mechanism ◽  
Bone Diseases ◽  
Orphan Nuclear Receptor ◽  
Low Bone Mass ◽  
Degenerative Disorders ◽  
Regulatory Loop

Osteoclasts are bone-resorbing cells essential for skeletal remodeling. However, over-active osteoclasts can cause bone-degenerative disorders. Therefore, the level of NFATc1, the master transcription factor of osteoclast, must be tightly controlled. Although the activation and amplification of NFATc1 have been extensively studied, how NFATc1 signaling is eventually resolved is unclear. Here, we uncover a novel and critical role of the orphan nuclear receptor Nur77 in mediating an NFATc1 self-limiting regulatory loop to prevent excessive osteoclastogenesis. Nur77 deletion leads to low bone mass owing to augmented osteoclast differentiation and bone resorption. Mechanistically, NFATc1 induces Nur77 expression at late stage of osteoclast differentiation; in turn, Nur77 transcriptionally up-regulates E3 ubiquitin ligase Cbl-b, which triggers NFATc1 protein degradation. These findings not only identify Nur77 as a key player in osteoprotection and a new therapeutic target for bone diseases, but also elucidate a previously unrecognized NFATc1→Nur77→Cblb—•NFATc1 feedback mechanism that confers NFATc1 signaling autoresolution.

scholarly journals Regulation of Osteoclast Differentiation and Activity by Lipid Metabolism

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 89
Author(s):  
Haemin Kim ◽  
Brian Oh ◽  
Kyung-Hyun Park-Min
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Bone Cells ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Metabolic Reprogramming ◽  
Lipid Lowering ◽  
Metabolic Bone Diseases ◽  
Increased Risk

Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions—such as atherosclerotic vascular disease, hyperlipidemia, and obesity—and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts.

scholarly journals CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

Open Biology ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 130217 ◽  
Author(s):  
Puneet Sharma ◽  
Alo Nag
Keyword(s):  
Ubiquitin Ligase ◽  
Drug Target ◽  
Critical Role ◽  
Cellular Transformation ◽  
Biological Processes ◽  
Molecular Architecture ◽  
The Past ◽  
Cullin 4A ◽  
Broad Overview

The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.

scholarly journals Role of pressure solution in the formation of bedding-parallel calcite veins in an immature shale (Cretaceous, southern UK)

2018 ◽  
Vol 156 (5) ◽  
pp. 918-934 ◽  
Author(s):  
QINGFENG MENG ◽  
JOHN HOOKER ◽  
JOE CARTWRIGHT
Keyword(s):  
Critical Role ◽  
Maximum Principal Stress ◽  
Feedback Mechanism ◽  
Black Shales ◽  
Pressure Solution ◽  
Overburden Pressure ◽  
Axis Orientation ◽  
Calcite Veins ◽  
Fibre Growth

AbstractBedding-parallel fibrous calcite veins in black shales (Cretaceous, southern UK) were investigated using a combined field, stable isotopic geochemistry, petrographic and crystallographic method to examine their formation mechanism. Calcite veins occur in all shale beds and are most abundant in the bituminous shales of the Chief Beef Beds. The calcite fibres in these veins exhibit either an antitaxial fibre growth with curvy stylolites as the median zone, or a predominantly syntaxial, upwards growth. The calcite veins range from –0.49 to 1.78‰ of δ13C values, and –6.53 to –0.03‰ of δ18O values, which are both similar to those of their host shales. Our petrographic observations demonstrate that subhorizontal and interconnecting microstylolite networks commonly occur within the calcite veins. Equant calcite grains in the median zones exhibit indenting, truncating and also interpenetrating grain contacts. It is interpreted that the fibrous calcite veins were sourced by neomorphic calcite from their host shales, with evidence from the δ13C signatures, pressure-solution features (stylolites, microstylolites and grain contact styles) and embedded fossil ghosts within the veins. The diagenetic fluids, from which calcite was precipitated, were a mixing of the original seawaters and 18O-depleted meteoric waters. Development of bedding-parallel calcite veins is considered to have been enhanced by pressure solution as a positive feedback mechanism, which was facilitated by the overburden pressure as the maximum principal stress. Calcite fibres, with a predominant subvertical c-axis orientation, exhibit a displacive growth in porous shales and a replacive growth at vein-limestone contacts. This study highlights the critical role of pressure solution in the formation of bedding-parallel calcite veins during burial and diagenesis of immature black shales.

Emerging Role of Extracellular Vesicles in Bone Remodeling

2018 ◽  
Vol 97 (8) ◽  
pp. 859-868 ◽  
Author(s):  
M. Liu ◽  
Y. Sun ◽  
Q. Zhang
Keyword(s):  
Bone Remodeling ◽  
Extracellular Vesicles ◽  
Transforming Growth Factor ◽  
Tooth Development ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Bone Diseases ◽  
Bioactive Molecules

Extracellular vesicles (EVs), as nanometer-scale particles, include exosomes, microvesicles, and apoptotic bodies. EVs are released by most cell types, such as bone marrow stem cells, osteoblasts, osteoclasts, and immune cells. In bone-remodeling microenvironments, EVs deliver specific proteins (e.g., tenascin C and Sema4D), microRNAs (e.g., miR-214-3p, miR-183-5p, and miR-196a), and other growth factors (e.g., bone morphogenetic protein 1 to 7 and transforming growth factor β1) to osteoblasts and regulate bone formation. In addition, EVs can deliver cytokines, such as RANK (receptor activator of nuclear factor κB) and RANKL (RANK ligand), and microRNAs, such as miR-218 and miR-148a, to modulate osteoclast differentiation during bone resorption. EVs also transfer bioactive molecules and have targeted therapies in bone-related diseases. Moreover, bioactive molecules in EVs are biomarkers in bone-related diseases. We highlight the emerging role of EVs in bone remodeling during physiologic and pathologic conditions and summarize the role of EVs in tooth development and regeneration. At the end of this review, we discuss the challenges of EV application in the treatment of bone diseases.

Abstract 174: The BH3-Only Protein BNIP3 Induces Mitochondrial Clearance via Multiple Pathways

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Eileen R Gonzalez ◽  
Babette Hammerling ◽  
Rita Hanna ◽  
Dieter A Kubli ◽  
Åsa B Gustafsson
Keyword(s):  
Cell Death ◽  
Ubiquitin Ligase ◽  
Critical Role ◽  
E3 Ubiquitin Ligase ◽  
Wild Type ◽  
Potent Inducer ◽  
Autophagy Pathway ◽  
Endosomal Pathway ◽  
In Cells

Autophagy plays an important role in cellular quality control and is responsible for removing protein aggregates and dysfunctional organelles. BNIP3 is an atypical BH3-only protein which is known to cause mitochondrial dysfunction and cell death in the myocardium. Interestingly, BNIP3 can also protect against cell death by promoting removal of dysfunctional mitochondria via autophagy (mitophagy). We have previously reported that BNIP3 is a potent inducer of mitophagy in cardiac myocytes and that BNIP3 contains an LC3 Interacting Region (LIR) that binds to LC3 on the autophagosome, tethering the mitochondrion to the autophagosome for engulfment. However, the molecular mechanism(s) underlying BNIP3-mediated mitophagy are still unclear. In this study, we discovered that BNIP3 can mediate mitochondrial clearance in cells even in the absence of a functional autophagy pathway. We found that overexpression of BNIP3 led to significant clearance of mitochondria in both wild type (WT) and autophagy deficient Atg5-/- MEFs. BNIP3 caused an increase in LC3II levels in WT MEFs, indicating increased formation of autophagosomes. In contrast, LC3II was undetectable in Atg5-/- MEFs. Furthermore, we found that BNIP3-mediated clearance in WT and Atg5-/- MEFs did not require the presence of Parkin, an E3 ubiquitin ligase which plays a critical role in clearing dysfunctional mitochondria in cells. Also, overexpression of Parkin did not enhance BNIP3-mediated mitochondrial clearance. When investigating activation of alternative cellular degradation pathways, we found that BNIP3 induced activation of the endosomal-lysosomal pathway in both WT and Atg5-/- MEFs. Mutating the LC3 binding site in BNIP3 did not interfere with the activation of the endosomal pathway and clearance of mitochondria in Atg5-/- MEFs. Thus, these findings suggest that BNIP3 can promote clearance of mitochondria via multiple pathways in cells. The role of autophagy in removing mitochondria is already well established and we are currently exploring the roles of the endosomal and alternative autophagy pathways in BNIP3-mediated mitochondrial clearance in myocytes.

scholarly journals Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

2020 ◽  
Vol 21 (10) ◽  
pp. 3486 ◽  
Author(s):  
Wen-Chih Liu ◽  
Jia-Fwu Shyu ◽  
Paik Seong Lim ◽  
Te-Chao Fang ◽  
Chien-Lin Lu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Indoxyl Sulfate ◽  
Raw 264.7 Cells ◽  
High Dose ◽  
Activated T Cells ◽  
Aryl Hydrocarbon

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

scholarly journals 3P218 Critical Role of osteopontin in osteoclast differentiation and activation

2005 ◽  
Vol 45 (supplement) ◽  
pp. S258
Author(s):  
K. Suzuki ◽  
Jaro Sodek ◽  
S. Yamada
Keyword(s):  
Critical Role ◽  
Osteoclast Differentiation

scholarly journals The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption

2021 ◽  
Vol 22 (13) ◽  
pp. 6934
Author(s):  
Anh Chu ◽  
Ralph A. Zirngibl ◽  
Morris F. Manolson
Keyword(s):  
Bone Resorption ◽  
Proton Translocation ◽  
Critical Role ◽  
Lipid Binding ◽  
Bone Diseases ◽  
Osteoclastic Bone Resorption ◽  
Subunit Structure ◽  
A Subunit ◽  
A3 Subunit

This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.

scholarly journals Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Sentiljana Gumeni ◽  
Eleni-Dimitra Papanagnou ◽  
Maria S. Manola ◽  
Ioannis P. Trougakos
Keyword(s):  
Critical Role ◽  
Model Organism ◽  
Dependent Manner ◽  
Degenerative Diseases ◽  
Knock Down ◽  
Age Related ◽  
Degenerative Disorders ◽  
Pathway Activation

AbstractThe balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.

The dramatic role of IFN family in aberrant inflammatory osteolysis

2020 ◽  
Vol 20 ◽  
Author(s):  
Zihan Deng ◽  
Wenhui Hu ◽  
Hongbo Ai ◽  
Yueqi Chen ◽  
Shiwu Dong
Keyword(s):  
Bone Resorption ◽  
Biological Activities ◽  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Bone Diseases ◽  
Therapeutic Effects ◽  
Type I ◽  
Type Iii

: Skeletal system has been considered as a highly dynamic system, in which bone-forming osteoblasts and boneresorbing osteoclasts go through continuous remodeling cycle to maintain homeostasis of bone matrix. It has been well acknowledged that interferons (IFNs), acting as a subgroup of cytokines, not only make crucial effects on regulating immunology, but also could modulate the dynamic balance of bone matrix. In the light of different isoforms, IFNs have been divided into three major categories in terms of amino acid sequences, recognition of specific receptors and biological activities. Currently, type I IFNs consist of a multi-gene family with several subtypes, of which IFN-α exerts proosteoblastogenic effects to activate osteoblast differentiation and inhibits osteoclast fusion to maintain bone matrix integrity. Meanwhile, IFN-β suppresses osteoblast-mediated bone remodeling as well as exhibits inhibitory effects on osteoclast differentiation to attenuate bone resorption. While type II IFN constitutes the only type, IFN-γ, which exerts regulatory effects on osteoclastic bone resorption and osteoblastic bone formation by biphasic ways. Interestingly, type III IFNs are regarded as new members of IFN family composed of four members, including IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, which have been certified to participate in bone destruction. However, the direct regulatory mechanisms underlying how type III IFNs modulate metabolic balance of bone matrix remains poorly elucidated. In this review, we have summarized functions of IFN family during physiological and pathological conditions and described the mechanisms by which IFNs maintain bone matrix homeostasis via affecting the osteoclast-osteoblast crosstalk. In addition, the potential therapeutic effects of IFNs on inflammatory bone destruction diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and infectious bone diseases are also well displayed, which are based on the predominant role of IFNs in modulating the dynamic equilibrium of bone matrix.

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