A band of F-actin containing podosomes is involved in bone resorption by osteoclasts

Kanehisa, Junya; Yamanaka, Takenori; Doi, Satoshi; Turksen, Kursad; Heersche, J. N. M.; Aubin, Jane E.; Takeuchi, Hiroshi

doi:10.1016/8756-3282(90)90082-a

Cited by 138 publications

(84 citation statements)

References 20 publications

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“…Early studies suggested the hypothesis that podosomes might represent precursors of sealing rings, based on the localization of podosome-like structures around resorption pits in fixed cells and on certain similarities in molecular composition (Kanehisa et al, 1990;Lakkakorpi and Vaananen, 1991). In contrast, in a recent study of living osteoclasts on mineralized substratum, actin sealing rings were observed by GFP-actin imaging, but podosomes were not seen (Saltel et al, 2004).…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

Tehrani¹,

Faccio

Chandrasekar³

et al. 2006

MBoC

126

117

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Osteoclasts are essential for bone dynamics and calcium homeostasis. The cells form a tight seal on the bone surface, onto which they secrete acid and proteases to resorb bone. The seal is associated with a ring of actin filaments. Cortactin, a c-Src substrate known to promote Arp2/3-mediated actin assembly in vitro, is expressed in osteoclasts and localizes to the sealing ring. To address the role of cortactin and actin assembly in osteoclasts, we depleted cortactin by RNA interference. Cortactin-depleted osteoclasts displayed a complete loss of bone resorption with no formation of sealing zones. On nonosteoid surfaces, osteoclasts flatten with a dynamic, actin-rich peripheral edge that contains podosomes, filopodia, and lamellipodia. Cortactin depletion led to a specific loss of podosomes, revealing a tight spatial compartmentalization of actin assembly. Podosome formation was restored in cortactin-depleted cells by expression of wild-type cortactin or a Src homology 3 point mutant of cortactin. In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation. Cortactin was found to be an early component of the nascent podosome belt, along with dynamin, supporting a role for cortactin in actin assembly.

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Section: Discussionmentioning

confidence: 88%

“…Osteoclasts form an integrinbased contact with the bone surface (Vaananen et al, 2000), which in association with actin forms a ring-shaped sealing zone (Kanehisa et al, 1990;Saltel et al, 2004). Osteoclasts secrete acid and proteases inside the sealing zone, which degrades the bone.…”

Section: Introductionmentioning

confidence: 99%

Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

Tehrani¹,

Faccio

Chandrasekar³

et al. 2006

MBoC

126

117

View full text Add to dashboard Cite

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“…Podosome rings also have a rapid turnover and occupy only a part of the ventral membrane in immature osteoclasts. Fusion of podosome rings results in a podosome belt that demarcates the cell periphery of differentiated osteoclasts on glass (Kanehisa et al, 1990). A podosome belt covers almost the whole ventral membrane and is stable over several hours.…”

Section: Introductionmentioning

confidence: 99%

The transient appearance of zipper-like actin superstructures during the fusion of osteoclasts

Takito

Nakamura

Yoda

et al. 2012

Journal of Cell Science

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SummaryMultinucleated osteoclasts are responsible for bone resorption. Hypermultinucleated osteoclasts are often observed in some bone-related diseases such as Paget's disease and cherubism. The cellular mechanics controlling the size of osteoclasts is poorly understood. We introduced EGFP-actin into RAW 264.7 cells to monitor actin dynamics during osteoclast differentiation. Before their terminal differentiation into osteoclasts, syncytia displayed two main types of actin assembly, podosome clusters and clusters of zipper-like structures. The zipper-like structures morphologically resembled the adhesion zippers found at the initial stage of cell-cell adhesion in keratinocytes. In the zipper-like structure, Arp3 and cortactin overlapped with the distribution of dense F-actin, whereas integrin b3, paxillin and vinculin were localized to the periphery of the structure. The structure was negative for WGA-lectin staining and biotin labeling. The zipper-like structure broke down and transformed into a large actin ring, called a podosome belt. Syncytia containing clusters of zipper-like structures had more nuclei than those with podosome clusters. Differentiated osteoclasts with a podosome belt also formed the zipper-like structure at the cell contact site during cell fusion. The breakdown of the cell contact site resulted in the fusion of the podosome belts following plasma membrane fusion. Additionally, osteoclasts in mouse calvariae formed the zipper-like structure in the sealing zone. Therefore, we propose that the zipper-like actin superstructures might be involved in cell-cell interaction to achieve efficient multinucleation of osteoclasts. Understanding of the zipper-like structure might lead to selective therapeutics for bone diseases caused by hypermultinucleated osteoclasts.

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“…oclasts-Osteoclasts plated on a glass coverslip demonstrate multiple actin-containing dot-like structures in the area corresponding to the clear zone of osteoclasts (3-5, 10, 61-63), whereas the resorbing osteoclasts demonstrated a band of Factin-containing podosomes (61,64). We have shown that OPN binding to the ␣ v ␤ 3 integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, FAK, c-Src, and PI3K (8,9).…”

Section: Immunofluorescent Staining Of Various Proteins In Oste-mentioning

confidence: 99%

Phosphatidylinositol 3,4,5-Trisphosphate Directs Association of Src Homology 2-containing Signaling Proteins with Gelsolin

Chellaiah¹,

Biswas²,

Yuen³

et al. 2001

Journal of Biological Chemistry

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Podosomes are adhesion structures in osteoclasts and are structurally related to focal adhesions mediating cell motility during bone resorption. Here we show that gelsolin coprecipitates some of the focal adhesion-associated proteins such as c-Src, phosphoinositide 3-kinase (PI3K), p130Cas , focal adhesion kinase, integrin ␣ v ␤ 3 , vinculin, talin, and paxillin. These proteins were inducibly tyrosine-phosphorylated in response to integrin activation by osteopontin. Previous studies have defined unique biochemical properties of gelsolin related to phosphatidylinositol 3,4,5-trisphosphate in osteoclast podosomes, and here we demonstrate phosphatidylinositol 3,4,5-trisphosphate/gelsolin function in mediating organization of the podosome signaling complex. Overlay and GST pull-down assays demonstrated strong phosphatidylinositol 3,4,5-trisphosphate-PI3K interactions based on the Src homology 2 domains of PI3K. Furthermore, lipid extraction of lysates from activated osteoclasts eliminated interaction between gelsolin, cSrc, PI3K, and focal adhesion kinase despite equal amounts of gelsolin in both the lipid-extracted and unextracted experiment. The cytoplasmic protein tyrosine phosphatase (PTP)-proline-glutamic acid-serine-threonine amino acid sequences (PEST) was also found to be associated with gelsolin in osteoclast podosomes and with stimulation of ␣ v ␤ 3 -regulated phosphorylation of PTP-PEST. We conclude that gelsolin plays a key role in recruitment of signaling proteins to the plasma membrane through phospholipid-protein interactions and by regulation of their phosphorylation status through its association with PTP-PEST. Because both gelsolin deficiency and PI3K inhibition impair bone resorption, we conclude that phosphatidylinositol 3,4,5-trisphosphate-based protein interactions are critical for osteoclast function.Osteoclasts are multinucleated giant cells with bone-resorbing activity. As osteoclasts crawl over bone surfaces, they require rapid attachment and release from the extracellular matrix. Adhesion structures called podosomes present in highly motile cells are also found in osteoclasts. Osteoclasts are unique because they use the speed of podosome assembly and disassembly to generate high rates of motility. Podosome formation stabilizes the bone matrix-cell interface and forms an isolated compartment between the ruffled border and the bone surface (1, 2). Consistent with their function as adhesion sites, podosomes contain many of the same proteins found in focal adhesions, such as F-actin, vinculin, talin, gelsolin, fimbrin, and ␣-actinin (3-7).We have shown previously that osteopontin (OPN) 1 binding to integrin ␣ v ␤ 3 in osteoclasts stimulates gelsolin-associated PI3K. This leads to increased levels of gelsolin-associated polyphosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P 2 ), phosphatidylinositol 3,4-bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate, uncapping of actin barbed ends, and actin filament formation (8). Moreover, OPN stimulates gelsolin-associ...

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A band of F-actin containing podosomes is involved in bone resorption by osteoclasts

Cited by 138 publications

References 20 publications

Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

The transient appearance of zipper-like actin superstructures during the fusion of osteoclasts

Phosphatidylinositol 3,4,5-Trisphosphate Directs Association of Src Homology 2-containing Signaling Proteins with Gelsolin

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