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1.
Role of full-length osteoprotegerin in tumor cell biology 总被引:1,自引:1,他引:0
G. Zauli E. Melloni S. Capitani P. Secchiero 《Cellular and molecular life sciences : CMLS》2009,66(5):841-851
Osteoprotegerin (OPG) is a soluble tumor necrosis factor receptor family member, which potently inhibits RANKL-mediated osteoclastogenesis.
Numerous constructs have been created for therapeutic purposes in which the heparin-binding and death homology domains of
OPG were removed and the remaining peptide (amino acids 22–194) was fused to the Fc domain of human IgG1 (OPG-Fc). The administration
of OPG-Fc efficiently counteracted bone loss in a variety of preclinical models of cancers. However, several in vitro studies have shown that native or recombinant full-length OPG not only neuralizes RANKL, but also the death-inducing ligand
TRAIL, suggesting that OPG might potentially counteract the anti-tumor activity of TRAIL. Additional evidence suggests that
full-length OPG possesses RANKL- and TRAIL-independent biological properties, mainly related to the promotion of endothelial
cell survival and angiogenesis. Finally, breast tumor cells overexpressing OPG have shown increased bone metastatic potential
in vivo. The relevance of these apparently conflicting findings in tumor cell biology is highlighted.
Received 2 September 2008; received after revision 29 September 2008; accepted 13 October 2008 相似文献
2.
Kyung-Hyun Park-Min 《Cellular and molecular life sciences : CMLS》2018,75(14):2519-2528
Osteoclasts are bone-resorbing cells that play an essential role in bone remodeling. Defects in osteoclasts result in unbalanced bone remodeling and are linked to many bone diseases including osteoporosis, rheumatoid arthritis, primary bone cancer, and skeletal metastases. Receptor activator of NF-kappaB ligand (RANKL) is a classical inducer of osteoclast formation. In the presence of macrophage-colony-stimulating factor, RANKL and co-stimulatory signals synergistically regulate osteoclastogenesis. However, recent discoveries of alternative pathways for RANKL-independent osteoclastogenesis have led to a reassessment of the traditional mechanisms that regulate osteoclast formation. In this review, we provide an overview of signaling pathways and other regulatory elements governing osteoclastogenesis. We also identify how osteoclastogenesis is altered in pathological conditions and discuss therapeutic targets in osteoclasts for the treatment of skeletal diseases. 相似文献
3.
Lubelski J Rink R Khusainov R Moll GN Kuipers OP 《Cellular and molecular life sciences : CMLS》2008,65(3):455-476
This review discusses the state-of-the-art in molecular research on the most prominent and widely applied lantibiotic, i.e., nisin. The developments in understanding its complex biosynthesis and mode of action are highlighted. Moreover, novel applications
arising from engineering either nisin itself, or from the construction of totally novel dehydrated and/or lanthionine-containing
peptides with desired bioactivities are described. Several challenges still exist in understanding the immunity system and
the unique multiple reactions occurring on a single substrate molecule, carried out by the dehydratase NisB and the cyclization
enzyme NisC. The recent elucidation of the 3-D structure of NisC forms the exciting beginning of further 3-D-structure determinations
of the other biosynthetic enzymes, transporters and immunity proteins. Advances in achieving in vitro activities of lanthionine-forming enzymes will greatly enhance our understanding of the molecular characteristics of the
biosynthesis process, opening up new avenues for developing unique and novel biocatalytic processes.
Received 9 April 2007; received after revision 31 August 2007; accepted 28 September 2007 相似文献
4.
Federica Corallini Paola Secchiero Antonio Paolo Beltrami Daniela Cesselli Elisa Puppato Roberto Ferrari Carlo Alberto Beltrami Giorgio Zauli 《Cellular and molecular life sciences : CMLS》2010,67(8):1307-1314
The number of circulating mesenchymal stem cells (MSC), analyzed after acute myocardial infarction (AMI), was lower in AMI
patients who developed heart failure (HF) in the follow-up. Conversely, the circulating levels of tumor necrosis factor (TNF)-α,
and osteoprotegerin (OPG) were higher in AMI patients who developed HF with respect to the patients who did not develop HF.
In vitro exposure to TNF-α enhanced the migration of MSC in response to TNF-related apoptosis-inducing ligand (TRAIL) and
significantly increased the release of OPG by endothelial cells. On the contrary, OPG dose-dependently neutralized the in
vitro pro-migratory activity of TRAIL. Thus, TNF-α exhibits opposite effects on MSC migration driven by TRAIL: it is capable
of potentiating MSC migration as well as of inhibiting MSC migration as an indirect consequence of OPG induction, which might
result in a suboptimal recruitment of circulating MSC after AMI in those patients who develop HF in the follow-up. 相似文献
5.
Se Hwan Mun Na Young Ko Hyuk Soon Kim Jie Wan Kim Do Kyun Kim A-Ram Kim Seung Hyun Lee Yong-Gil Kim Chang Keun Lee Seoung Hoon Lee Bo Kyung Kim Michael A. Beaven Young Mi Kim Wahn Soo Choi 《Cellular and molecular life sciences : CMLS》2010,67(22):3883-3892
Interleukin (IL)-33 is a recently described pro-inflammatory cytokine. Here we demonstrate IL-33 as a regulator of functional osteoclasts (OCs) from human CD14+ monocytes. IL-33 stimulates formation of tartrate-resistant acid phosphatase (TRAP)+ multinuclear OCs from monocytes. This action was suppressed by anti-ST2 antibody, suggesting that IL-33 acts through its receptor ST2, but not by the receptor activator of NF-κB ligand (RANKL) decoy, osteoprotegerin, or anti-RANKL antibody. IL-33 stimulated activating phosphorylations of signaling molecules in monocytes that are critical for OC development. These included Syk, phospholipase Cγ2, Gab2, MAP kinases, TAK-1, and NF-κB. IL-33 also enhanced expression of OC differentiation factors including TNF-α receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor. IL-33 eventually induced bone resorption. This study suggests that the osteoclastogenic property of IL-33 is mediated through TRAF6 as well as the immunoreceptor tyrosine-based activation motif-dependent Syk/PLCγ pathway in human CD14+ monocytes. 相似文献
6.
7.
Duration of bone protection by a single osteoprotegerin injection in rats with adjuvant-induced arthritis 总被引:6,自引:0,他引:6
Daily osteoprotegerin (OPG) injection for 7 or more days prevents bone loss for 3 weeks in rats with adjuvant-induced arthritis (AdA). The present experiments defined the duration of bone protection in AdA provided by a single OPG bolus. Male Lewis rats received OPG at the onset or peak of clinical disease, after which bone mineral density (BMD), erosions, and osteoclasts were evaluated. An OPG bolus (4 mg/kg subcutaneously) at onset eliminated osteoclasts, preserved BMD for 7 days, and prevented bone erosions for 4 days. In contrast, an OPG bolus (1, 3, 10, or 30 mg/kg intravenously) given at the peak of disease eradicated osteoclasts in a dose-dependent manner but had no impact on bone integrity due to extensive pre-existing bone loss. These data indicate that one OPG injection will inhibit joint erosions for several days, and confirm that bone-sparing therapy must be initiated early in disease to protect joint integrity. 相似文献
8.
9.
de Wit PJ 《Cellular and molecular life sciences : CMLS》2007,64(21):2726-2732
Plants have an innate immunity system to defend themselves against pathogens. With the primary immune system, plants recognize
microbe-associated molecular patterns (MAMPs) of potential pathogens through pattern recognition receptors (PRRs) that mediate
a basal defense response. Plant pathogens suppress this basal defense response by means of effectors that enable them to cause
disease. With the secondary immune system, plants have gained the ability to recognize effector-induced perturbations of host
targets through resistance proteins (RPs) that mediate a strong local defense response that stops pathogen growth. Both primary
and secondary immune responses in plants depend on germ line-encoded PRRs and RPs. During induction of local immune responses,
systemic immune responses also become activated, which predispose plants to become more resistant to subsequent pathogen attacks.
This review gives an update on recent findings that have enhanced our understanding of plant innate immunity and the arms
race between plants and their pathogens.
Received 24 June 2007; received after revision 18 July 2007; accepted 15 August 2007 相似文献
10.
11.
Mar Orriols Maria Catalina Gomez-Puerto Peter ten Dijke 《Cellular and molecular life sciences : CMLS》2017,74(16):2979-2995
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies. 相似文献
12.
Molecular mechanisms of lymphatic vascular development 总被引:8,自引:1,他引:7
Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the
maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor
metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as
VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation
for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize
recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.
Received 26 January 2007; received after revision 5 March 2007; accepted 29 March 2007 相似文献
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14.
Multiple cellular functions of urokinase and its receptor are associated with the receptor’s capability to interact with a
number of ligands at the molecular level. The presence of urokinase is generally needed for the urokinase receptor to acquire
this capability. Recent X-ray studies of the structure of the urokinase receptor in complex with either its ligand or peptide
inhibitors demonstrate the flexibility of the domain organization of the receptor, suggesting that unliganded urokinase receptor
may exist in a latent form that has a conformation different from its ligand-binding form.
Received 22 November 2006; received after revision 8 January 2007; accepted 7 February 2007 相似文献
15.
Leonard Girnita Claire Worrall Shin-Ichiro Takahashi Stefan Seregard Ada Girnita 《Cellular and molecular life sciences : CMLS》2014,71(13):2403-2427
The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and progression of cancer; however, therapeutics targeting it have had disappointing results in the clinic. As a receptor tyrosine kinase (RTK), IGF-1R is traditionally described as an ON/OFF system, with ligand stabilizing the ON state and exclusive kinase-dependent signaling activation. Newly added to the traditional model, ubiquitin-mediated receptor downregulation and degradation was originally described as a response to ligand/receptor interaction and thus inseparable from kinase signaling activation. Yet, the classical model has proven over-simplified and insufficient to explain experimental evidence accumulated over the last decade, including kinase-independent signaling, unbalanced signaling, or dissociation between signaling and receptor downregulation. Based on the recent findings that IGF-1R “borrows” components of G-protein coupled receptor (GPCR) signaling, including β-arrestins and G-protein-related kinases, we discuss the emerging paradigm for the IGF-1R as a functional RTK/GPCR hybrid, which integrates the kinase signaling with the IGF-1R canonical GPCR characteristics. The contradictions to the classical IGF-1R signaling concept as well as the design of anti-IGF-1R therapeutics treatment are considered in the light of this paradigm shift and we advocate recognition of IGF-1R as a valid target for cancer treatment. 相似文献
16.
Reverse signaling using an inducible costimulator to enhance immunogenic function of dendritic cells
Gusheng Tang Qin Qin Peng Zhang Guifang Wang Menglei Liu Qingli Ding Yanghua Qin Qian Shen 《Cellular and molecular life sciences : CMLS》2009,66(18):3067-3080
A costimulatory signal from an inducible costimulator (ICOS) of T cells plays a critical role in immunological homeostasis.
This study shows that the interaction of ICOSIg and its ligand (ICOSL) on mouse bone marrow-derived dendritic cells (DCs)
induces a p38-MAPK dependent elevation of interleukin 6 (IL-6). It also enhances phagocytosis and the antigen-presentation
function of DCs in vitro, further favoring cell-mediated immunity in vivo. As seen for other types of costimulator molecules
expressed in the T cells in the CD28 family, it is shown here for the first time that ICOS can also deliver reverse signals
through its ligand to ICOSL-expressing cells. These reverse signals in turn transfer positive immunogenic information to bone
marrow-derived DCs. Our work therefore provides new recognition of an ICOSL/ICOS signal pathway in immunity and also supplies
more evidence that this ICOSL/ICOS signal pathway is a reasonable target for therapeutic drugs. 相似文献
17.
Franky Van Herreweghe Nele Festjens Wim Declercq Peter Vandenabeele 《Cellular and molecular life sciences : CMLS》2010,67(10):1567-1579
In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor
(TNF): cell survival through NF-κB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial
role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative
cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome.
TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine
kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as
a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between
cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology
and pathogenesis of human diseases. 相似文献
18.
Serine peptidases: Classification, structure and function 总被引:1,自引:1,他引:0
Serine peptidases play key roles in human health and disease and their biochemical properties shaped the molecular evolution
of these processes. Of known proteolytic enzymes, the serine peptidase family is the major cornerstone of the vertebrate degradome.
We describe the known diversity of serine peptidases with respect to structure and function. Particular emphasis is placed
on the S1 peptidase family, the trypsins, which underwent the most predominant genetic expansion yielding the enzymes responsible
for vital processes in man such as digestion, blood coagulation, fibrinolysis, development, fertilization, apoptosis and immunity.
Received 13 December 2007; received after revision 8 January 2008; accepted 22 January 2008 相似文献
19.
Zhenhua Luo Yao Liu Yitong Liu Hui Chen Songtao Shi Yi Liu 《Cellular and molecular life sciences : CMLS》2017,74(24):4443-4453
Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs. 相似文献
20.
Albrecht M Frungieri MB Kunz L Rämsch R Meineke V Köhn FM Mayerhofer A 《Cellular and molecular life sciences : CMLS》2005,62(23):2867-2876
Fibroblast proliferation is a key process in tissue remodeling and mast cells (MCs) are thought to play a crucial role. Having
established that the three major MC products, tryptase, histamine and TNF-alpha (TNF) are normally present in human skin MCs,
which are in close proximity to dermal fibroblasts, we studied their individual effects on cell cycle-controlled human dermal
fibroblasts (HFFF2). These cells express receptors (H1, PAR2, TNFR1/2) for the major MC mediators, but only tryptase or a
PAR2 agonist peptide stimulated proliferation and gene expression. TNF was antimitotic, and histamine, while elevating intracellular
Ca2+ levels at high concentrations, did not affect proliferation. We conclude that MC products but also composition and numbers
of respective receptors on fibroblasts are crucially responsible for fibroproliferative events.
Received: 28 June 2005; received after revision 28 September 2005; accepted 6 October 2005 相似文献