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Biochemical and Biophysical Research... Jul 2016Bone resorption is an important cellular function in skeletal development and remodeling of the adult skeleton. Most of the pathological bone disease conditions like... (Review)
Review
Bone resorption is an important cellular function in skeletal development and remodeling of the adult skeleton. Most of the pathological bone disease conditions like osteoporosis reflect increased osteoclast activity; hence, increased bone resorption. Researchers have unraveled most of the intracellular mechanisms responsible for osteoclast bone-resorbing activity in last few decades. Therefore, understanding the fundamentals of osteoclast-induced bone resorption and the cytokines and other substances that modulate the osteoclast activity unequivocally provide insights into the development of drugs to ameliorate pathological bone diseases with enhanced bone resorption. The aim of this review is to examine the literature on osteoclast function and bone-resorbing activity.
Topics: Animals; Bone Resorption; Cell Adhesion; Humans; Integrins; Osteoclasts; Podosomes; Signal Transduction
PubMed: 27157135
DOI: 10.1016/j.bbrc.2016.05.019 -
Experimental & Molecular Medicine Mar 2022Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate...
Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD.
Topics: Animals; Cell Adhesion; Cresols; Cytoskeletal Proteins; Humans; Indican; Mice; Monocytes; Podosomes; Protein Serine-Threonine Kinases; THP-1 Cells
PubMed: 35246616
DOI: 10.1038/s12276-022-00738-8 -
Cell Cycle (Georgetown, Tex.) 2015The vascular basement membrane (BM) is a thin and dense cross-linked extracellular matrix layer that covers and protects blood vessels. Understanding how cells cross the... (Review)
Review
The vascular basement membrane (BM) is a thin and dense cross-linked extracellular matrix layer that covers and protects blood vessels. Understanding how cells cross the physical barrier of the vascular BM will provide greater insight into the potentially critical role of vascular BM breaching in cancer extravasation, leukocyte trafficking and angiogenic sprouting. In the last year, new evidence has mechanistically linked the breaching of vascular BM with the formation of specific cellular micro-domains known as podosomes and invadopodia. These structures are specialized cell-matrix contacts with an inherent ability to degrade the extracellular matrix. Specifically, the formation of podosomes or invadopodia was shown as an important step in vascular sprouting and tumor cell extravasation, respectively. Here, we review and comment on these recent findings and explore the functions of podosomes and invadopodia within the context of pathological processes such as tumor dissemination and tumor angiogenesis.
Topics: Angiogenic Proteins; Animals; Basement Membrane; Blood Vessels; Cell Movement; Extracellular Matrix Proteins; Humans; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Podosomes
PubMed: 25789660
DOI: 10.1080/15384101.2015.1026523 -
European Journal of Cell Biology Oct 2014Podosomes and invadopodia, collectively known as invadosomes, are specialized cell-matrix contacts with an inherent ability to degrade extracellular matrix. Their... (Review)
Review
Podosomes and invadopodia, collectively known as invadosomes, are specialized cell-matrix contacts with an inherent ability to degrade extracellular matrix. Their occurrence in either normal (podosomes) or cancer cells (invadopodia) is thus traditionally associated with cell invasiveness and tissue remodelling. These specialized micro-domains of the plasma membrane are characterized by enrichment of F-actin, cortactin and metalloproteases. Recent developments in the field show that, under some circumstances, vascular endothelial cells (ECs) can be induced to form this kind of peculiar structures. Cultured ECs contain either 0.5-1-μm-wide individual podosomes or 5 to 10 μm wide ring-like clusters of podosomes (podosome rosettes). The formation of individual podosomes or podosome rosettes in ECs can be induced by soluble factors, such as TGFβ, VEGF, TNFα or pharmacological agents, such as phorbol esters. Recently, the evidence of the existence of such structures in vascular endothelium has been provided by ex vivo observation. Endothelial podosome rosettes have recently been functionally linked to arterial remodelling and sprouting angiogenesis. Concerted efforts aim now at confirming the relevance of endothelial podosomes in these patho-physiological processes in vivo. In the current review, we will introduce some general considerations regarding ECs in the vascular system. From there on, we will review the various EC types where podosomes have been described and the state-of-art knowledge hitherto generated regarding endothelial podosome features.
Topics: Animals; Cell Surface Extensions; Endothelial Cells; Humans; Inflammation; Ischemia; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 25199436
DOI: 10.1016/j.ejcb.2014.07.009 -
The FEBS Journal Jan 2018Invadopodia and podosomes are discrete, actin-based molecular protrusions that form in cancer cells and normal cells, respectively, in response to diverse signaling... (Review)
Review
Invadopodia and podosomes are discrete, actin-based molecular protrusions that form in cancer cells and normal cells, respectively, in response to diverse signaling pathways and extracellular matrix cues. Although they participate in a host of different cellular processes, they share a common functional theme of controlling pericellular proteolytic activity, which sets them apart from other structures that function in migration and adhesion, including focal adhesions, lamellipodia, and filopodia. In this review, we highlight research that explores the function of these complex structures, including roles for podosomes in embryonic and postnatal development, in angiogenesis and remodeling of the vasculature, in maturation of the postsynaptic membrane, in antigen sampling and recognition, and in cell-cell fusion mechanisms, as well as the involvement of invadopodia at multiple steps of the metastatic cascade, and how all of this may apply in the treatment of human disease states. Finally, we explore recent research that implicates a novel role for exosomes and microvesicles in invadopodia-dependent and invadopodia-independent mechanisms of invasion, respectively.
Topics: Animals; Cell Surface Extensions; Exosomes; Focal Adhesions; Humans; Neoplasm Invasiveness; Neoplasms; Podosomes; Pseudopodia
PubMed: 28548369
DOI: 10.1111/febs.14123 -
BioEssays : News and Reviews in... Aug 2023During immune responses against invading pathogenic bacteria, the cytoskeleton network enables macrophages to implement multiple essential functions. To protect the host... (Review)
Review
During immune responses against invading pathogenic bacteria, the cytoskeleton network enables macrophages to implement multiple essential functions. To protect the host from infection, macrophages initially polarize to adopt different phenotypes in response to distinct signals from the microenvironment. The extracellular stimulus regulates the rearrangement of the cytoskeleton, thereby altering the morphology and migratory properties of macrophages. Subsequently, macrophages degrade the extracellular matrix (ECM) and migrate toward the sites of infection to directly contact invading pathogens, during which the involvement of cytoskeleton-based structures such as podosomes and lamellipodia is indispensable. Ultimately, macrophages execute the function of phagocytosis to engulf and eliminate the invading pathogens. Phagocytosis is a complex process that requires the cooperation of cytoskeleton-enriched super-structures, such as filopodia, lamellipodia, and phagocytic cup. This review presents an overview of cytoskeletal regulations in macrophage polarization, ECM degradation, migration, and phagocytosis, highlighting the pivotal role of the cytoskeleton in host defense against infection.
Topics: Macrophages; Cytoskeleton; Phagocytosis; Cell Membrane; Microtubules
PubMed: 37254735
DOI: 10.1002/bies.202200225 -
International Journal of Molecular... Jan 2019Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of... (Review)
Review
Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf GAP activity. A number of these functions hinge on the remodeling of actin filaments. Accordingly, some of the effects exerted by Arf GAPs involve proteins known to engage in regulation of the actin dynamics and architecture, such as Rho family proteins and nonmuscle myosin 2. Circular dorsal ruffles (CDRs), podosomes, invadopodia, lamellipodia, stress fibers and focal adhesions are among the actin-based structures regulated by Arf GAPs. Arf GAPs are thus important actors in broad functions like adhesion and motility, as well as the specialized functions of bone resorption, neurite outgrowth, and pathogen internalization by immune cells. Arf GAPs, with their multiple protein-protein interactions, membrane-binding domains and sites for post-translational modification, are good candidates for linking the changes in actin to the membrane. The findings discussed depict a family of proteins with a critical role in regulating actin dynamics to enable proper cell function.
Topics: ADP-Ribosylation Factors; Actin Cytoskeleton; Actins; Animals; Apoptosis; Cell Movement; Focal Adhesions; GTPase-Activating Proteins; Host-Pathogen Interactions; Humans; Multigene Family; Neuronal Outgrowth; Neurons; Podosomes; Protein Binding; Pseudopodia; Structure-Activity Relationship; rho GTP-Binding Proteins
PubMed: 30669557
DOI: 10.3390/ijms20020442 -
Communications Biology Mar 2020Integrin receptors orchestrate cell adhesion and cytoskeletal reorganization. The endocytic mechanism of integrin-β3 receptor at the podosome remains unclear. Using...
Integrin receptors orchestrate cell adhesion and cytoskeletal reorganization. The endocytic mechanism of integrin-β3 receptor at the podosome remains unclear. Using viscous RGD-membrane as the model system, here we show that the formation of podosome-like adhesion promotes Dab2/clathrin-mediated endocytosis of integrin-β3. Integrin-β3 and RGD ligand are endocytosed from the podosome and sorted into the endosomal compartment. Inhibitions of podosome formation and knockdowns of Dab2 and clathrin reduce RGD endocytosis. F-actin assembly at the podosome core exhibits protrusive contact towards the substrate and results in plasma membrane invaginations at the podosome ring. BIN1 specifically associates with the region of invaginated membrane and recruits DNM2. During the podosome formation, BIN1 and DNM2 synchronously enrich at the podosome ring and trigger clathrin dissociation and RGD endocytosis. Knockdowns of BIN1 and DNM2 suppress RGD endocytosis. Thus, plasma membrane invagination caused by F-actin polymerization promotes BIN1-dependent DNM2 recruitment and facilitate integrin-β3 endocytosis at the podosome.
Topics: Actins; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Cell Adhesion; Cell Membrane; Cells, Cultured; Clathrin; Dynamin II; Endocytosis; Fibroblasts; Gene Knockdown Techniques; Humans; Integrin beta3; Ligands; Membranes, Artificial; Mice; Nerve Tissue Proteins; Oligopeptides; Podosomes; Polymerization; Rats; Transfection; Tumor Suppressor Proteins
PubMed: 32170110
DOI: 10.1038/s42003-020-0843-2 -
Cell & Bioscience May 2023Tau protein forms neurofibrillary tangles and becomes deposited in the brain during Alzheimer's disease (AD). Tau oligomers are the most reactive species, mediating...
BACKGROUND
Tau protein forms neurofibrillary tangles and becomes deposited in the brain during Alzheimer's disease (AD). Tau oligomers are the most reactive species, mediating neurotoxic and inflammatory activity. Microglia are the immune cells in the central nervous system, sense the extracellular Tau via various cell surface receptors. Purinergic P2Y12 receptor can directly interact with Tau oligomers and mediates microglial chemotaxis via actin remodeling. The disease-associated microglia are associated with impaired migration and express a reduced level of P2Y12, but elevate the level of reactive oxygen species and pro-inflammatory cytokines.
RESULTS
Here, we studied the formation and organization of various actin microstructures such as-podosome, filopodia and uropod in colocalization with actin nucleator protein Arp2 and scaffold protein TKS5 in Tau-induced microglia by fluorescence microscopy. Further, the relevance of P2Y12 signaling either by activation or blockage was studied in terms of actin structure formations and Tau deposits degradation by N9 microglia. Extracellular Tau oligomers facilitate the microglial migration via Arp2-associated podosome and filopodia formation through the involvement of P2Y12 signaling. Similarly, Tau oligomers induce the TKS5-associated podosome clustering in microglial lamella in a time-dependent manner. Moreover, the P2Y12 was evidenced to localize with F-actin-rich podosome and filopodia during Tau-deposit degradation. The blockage of P2Y12 signaling resulted in decreased microglial migration and Tau-deposit degradation.
CONCLUSIONS
The P2Y12 signaling mediate the formation of migratory actin structures like- podosome and filopodia to exhibit chemotaxis and degrade Tau deposit. These beneficial roles of P2Y12 in microglial chemotaxis, actin network remodeling and Tau clearance can be intervened as a therapeutic target in AD.
PubMed: 37221563
DOI: 10.1186/s13578-023-01028-0 -
Annual Review of Biomedical Engineering Jun 2019In addition to their early-recognized functions in host defense and the clearance of apoptotic cell debris, macrophages play vital roles in tissue development,... (Review)
Review
In addition to their early-recognized functions in host defense and the clearance of apoptotic cell debris, macrophages play vital roles in tissue development, homeostasis, and repair. If misregulated, they steer the progression of many inflammatory diseases. Much progress has been made in understanding the mechanisms underlying macrophage signaling, transcriptomics, and proteomics, under physiological and pathological conditions. Yet, the detailed mechanisms that tune circulating monocytes/macrophages and tissue-resident macrophage polarization, differentiation, specification, and their functional plasticity remain elusive. We review how physical factors affect macrophage phenotype and function, including how they hunt for particles and pathogens, as well as the implications for phagocytosis, autophagy, and polarization from proinflammatory to prohealing phenotype. We further discuss how this knowledge can be harnessed in regenerative medicine and for the design of new drugs and immune-modulatory drug delivery systems, biomaterials, and tissue scaffolds.
Topics: Animals; Anti-Bacterial Agents; Apoptosis; Biocompatible Materials; Biophysics; Cell Differentiation; Disease Progression; Drug Delivery Systems; Humans; Immunologic Factors; Inflammation; Macrophages; Mice; Phagocytosis; Podosomes; Proteomics; Regenerative Medicine; Signal Transduction; Tissue Engineering; Tissue Scaffolds; Transcriptome; Wound Healing
PubMed: 31167103
DOI: 10.1146/annurev-bioeng-062117-121224