Podosomes are conical,

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

-rich structures found on the outer surface of the plasma membrane of

animal cells The cell is the basic structural and functional unit of life forms. Every cell consists of a cytoplasm enclosed within a membrane, and contains many biomolecules such as proteins, DNA and RNA, as well as many small molecules of nutrients an ...

. Their size ranges from approximately 0.5 µm to 2.0 µm in diameter. While usually situated on the periphery of the cellular membrane, these unique structures display a polarized pattern of distribution in migrating cells, situating at the front border between the

lamellipodium The lamellipodium (plural lamellipodia) (from Latin ''lamella'', related to ', "thin sheet", and the Greek radical ''pod-'', "foot") is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional ...

and lamellum. Their primary purpose is connected to cellular

motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

and invasion; therefore, they serve as both sites of attachment and degradation along the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

. Many different specialized cells exhibit these dynamic structures such as invasive

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cells,

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...

, vascular smooth muscle cells,

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

, and certain immune cells like

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

Characteristics

A podosome consists of a core rich in actin surrounded by adhesion and scaffolding proteins. The actin filaments within these structures are highly regulated by many actin nucleators, polymerization activators, actin binding and crosslinking proteins,

kinases In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

, small GTPases, and scaffold proteins; therefore, total actin turnover occurs within seconds. To distinguish podosomes from others types of cellular adhesions, the protein Tks5 and WASP (

Wiskott–Aldrich syndrome protein The Wiskott–Aldrich Syndrome protein (WASp) is a 502-amino acid protein expressed in cells of the hematopoietic system that in humans is encoded by the ''WAS'' gene. In the inactive state, WASp exists in an autoinhibited conformation with sequ ...

) are used as markers alongside

cortactin Cortactin (from "''cortical actin'' binding protein") is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin c ...

and the

Arp2/3 complex Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most actin cytoskeleton ...

to localize and isolate these protrusions because Tks5 and WASP are unique to the podosome when compared with other actin-based cellular structures. In their outward structure, the podosomes demonstrate two distinct features: an actin core and a ring complex. Within the core, coordinators of actin nucleation are found. Specifically, the

and WASP when close to the plasma membrane or cortactin when further away comprise this group of proteins. Emanating radially from the dense core of actin are actin filaments reaching to the plasma membrane and between neighboring podosomes. In the ring complex,

integrins Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

and integrin-associated proteins serve to connect the cytoskeleton to cell surface integrins forming the outward protrusion. Initial research suggested that the superstructure of podosomes were cylindrical, but new advances in bioimaging techniques have altered that perception and show the ring complex to display a

polygonal In geometry, a polygon () is a plane figure that is described by a finite number of straight line segments connected to form a closed ''polygonal chain'' (or ''polygonal circuit''). The bounded plane region, the bounding circuit, or the two to ...

form. These finding were made possible through the application of Bayesian blinking and bleaching analytics to data gained from standard widefield microscopy using cells that expressed fluorescently tagged proteins specific to the podosome ring complex. Typically, the podosome size falls between 0.5 um and 2.0 um in diameter and depth. The lifetime of the structure is only minutes in duration, much shorter than observed in invadopodia.

Function

Podosomes are thought to be intimately connected to cellular motility within tissue microenvironments through coordinating degradation of the extracellular matrix with cellular movement. The migration of cells is essential to proper embryonic development and, in maturity, to

wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...

and the

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

. Examples of these motile cell behaviors include: transendothelial migration of dendritic cells, migration of aortic endothelial cells for arterial vessel remodeling, and tissue infiltration by macrophages. Aberrations in cell migration lie beneath pathologies involving development, vasculature, and immunity. Consequently, podosomes are present in cell types associated with tissue remodeling and the immune system. Patients who suffer from

Wiskott–Aldrich syndrome Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczem ...

demonstrate, through their immune cells, continued evidence of the role podosomes fulfill in cell motility. These patients do not possess fully formed WASP that has been shown to localize in podosomes and to be integral to their formation from previous studies. The dendritic cells and macrophages of these patients’ immune systems do not manifest podosome formations and demonstrate defects in cellular movement within tissue microenvironments. Some researchers suspect that podosomes may be implicated in the migration of neural crest cells. Patients who exhibit Frank–ter Haar syndrome are known to be mutant for the podosome specific protein Tks4 and demonstrate defects in

neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...

cell migration.
Adding to the known functionalities of podosomes, research suggests that these dynamic structures also exhibit mechanosensory attributes. Initial formation of podosomes seems to be influenced by the structure and composition of the underlying substratum including the presence and distribution of specific ligands. Various integrin receptors monitor the mechanical properties of the cellular microenvironment and can influence and initiate formation of a podosome. Once fully formed, the integrity of the matrix substratum dictates the lifespan of the podosome with increased stiffness leading to longer endurance and closer spacing between podosome sites. Some studies indicates also a putative role for podosomes even in the regulation of bone marrow stem cell's function. Podosomes have been shown to be widely present ''in vitro'' on mesodermal progenitor cells (MPCs), cell capable of differentiating into mesenchymal stromal cells. It has been proposed that podosomes are important in the mobilisation of MPCs in the event of physiological need.

Role in osteoclasts

Osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...

are large, multinucleated bone cells that conduct the process of

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

. In this remodeling process, podosomes play an integral role. During the maturation of osteoclast precursors, groups of podosomes form higher ordered ring structures which ultimately coalesce into a band about the cell periphery. The resulting arrangement of podosomes is highly interconnected through a dense, radial network of actin filaments that extend between and onto neighboring podosomes. Accumulation of

F-actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

vinculin In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cel ...

paxillin Paxillin is a protein that in humans is encoded by the ''PXN'' gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutation ...

, and α-actin within the podosomes of the coalescent band signals the development of a fully matured osteoclast. Upon initiation of bone resorption, the band of podosomes disassembles leaving behind a mesh primarily composed of F-actin which functions as the ‘sealing zone.’ This sealing zone becomes the site of osteoclast attachment to the bone matrix. Inhibition of bone resorption through drug intervention results in the lack of the podosome band during early osteoclast differentiation and ultimate absence of a sealing zone.

History

In the early 1980s, chicken embryo

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

were transformed using the Rous sarcoma virus (RSV) containing the oncogene v-src. This transformation elicited the relocalization of

and α-actin in the

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...

from

focal adhesions In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More ...

forming circular clusters. Later in 1985, it was shown using the same cells that these protein clusters were localized to protrusions in the ventral plasma membrane, were substratum adhesion sites; therefore, these structures were termed podosomes indicating their foot-like character in cells. In 1989, it was demonstrated that these podosomes played a role in matrix degradation. To reflect this newly discovered destructive nature the name invadopodia was given to these dynamic structures. Because both terms invadopodia and podosomes were initially used to reference the identical structures in identical cell lines, there exists confusion about the nomenclature. Typically, when these structures are found in normal cells, they are referred to as podosomes, and when in cancer cells, invadopodia.

References

External links