Cytoskeleton Dynamics

What are the functions of podosomes?

Both focal adhesions and podosomes are intimately involved in cell motility, with podosomes specifically implicated in cell invasion. Invasiveness is achieved through the secretion of matrix metalloproteinases (MMPs) from the core of podosomes, which degrade the extracellular matrix (ECM). This promotes motile behaviors that aid a range of processes including; transendothelial migration (diapedesis) of dendritic cells [1], migration of aortic endothelial cells for arterial vessel remodeling [2] and tissue infiltration by macrophages [3].

Further evidence for the role of podosomes in cell migration, comes from the immune cells of Wiskott-Aldrich Syndrome patients. These patients lack full length WASP(Wiskott-Aldrich Syndrome protein), which is known to localize to podosomes and is required for their formation. Both the dendritic cells [4] and macrophages [5] of these patients lack podosomes and as a consequence show migratory defects [4][5]. There is currently speculation that podosomes may also be important in the migration of neural crest cells, due to the neural crest-associated defects seen in Frank-ter Haar patients, who are mutant for the podosome- and invadopodia-specific protein Tks5 [6].

In addition to the roles ascribed above, the idea of podosomes having mechanosensory potential has also been posited [7][8][9][10]. The initiation of podosome formation has been shown to be dependent on the underlying matrix, both in terms of its nature (which ligands are present) and its geometry (whether the ligands are uniformly distributed or arranged in subcellular-sized islands). Cells use different integrin receptors to detect the mechanical constraints of their environment and to decide accordingly whether a podosome should be initiated or not [8]. Following initiation, substrate stiffness continues to play a role in the lifespan of the podosome, with increased stiffness resulting in increased longevity and decreased distance between individual podosomes [9].

Once formed, the podosome itself is hypothesized to exhibit mechanosensory characteristics, transmitting mechanical forces both from the inside-out and outside-in [7]. This was suggested following a series of experiments examining the actomyosin network of the podosome. Myosin II was detected in and around the adhesive ring of the podosome. Changes in the size and shape of the adhesive ring were shown to result in changes in tractional forces against the underlying substrate (inside-out force transmission), in a myosin-dependent manner. Moreover, increasing substrate stiffness, increased the strength of these tractional forces (outside-in force transmission).

Podosomes in osteoclast function

Osteoclasts are multinucleated, bone-resorbing cells that use podosomes for bone remodeling. During the process of differentiation from osteoclast precursors to mature osteoclasts, clusters of podosomes rearrange themselves into higher order rings structures, which are finally reorganized into a single belt around the cell periphery [11]. These structures are highly interconnected due to a dense network of radial actin filaments that connect the composite podosomes to each other [12].

The structural changes that occur during osteoclast maturation involve the accumulation of F-actin, vinculin, paxillin and α-actinin specifically within podosomes of the forming ring structure [13]. Signaling changes also occur within these podosomes, such as reduced levels of Src-mediated phosphorylation [13]. The podosome protein, cortactin, specifically shows reduced levels of tyrosine phosphorylation, which is suggested to enhance its actin-nucleating activity [14].

Upon bone resorption, the podosome belt is dismantled, leaving behind a ring-like F-actin mesh encompassing the ‘sealing zone’ [15]. The sealing zone forms the attachment of the osteoclast to the underlying bone and is essential to the process of bone resorption. The inhibition of bone resorption by drug treatment results in loss of the characteristic podosome belt around the cell periphery. Podosomes are therefore believed to play an important role in formation of the sealing zone and bone resorption [15].

References

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2. Rottiers P, Saltel F, Daubon T, Chaigne-Delalande B, Tridon V, Billottet C, Reuzeau E, and Génot E. TGFbeta-induced endothelial podosomes mediate basement membrane collagen degradation in arterial vessels. J. Cell. Sci. 2009; 122(Pt 23):4311-8. [PMID: 19887587]
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14. Luxenburg C, Parsons JT, Addadi L, and Geiger B. Involvement of the Src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts. J. Cell. Sci. 2006; 119(Pt 23):4878-88. [PMID: 17105771]
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