Cellular and Molecular Biology of the Osteoclast

Baron, Roland; Ravesloot, Jan H.; Neff, Lynn; Chakraborty, Munmun; Chatterjee, Diptendu; Lomri, Abderrahim; Horne, William C.

doi:10.1016/b978-0-08-092500-4.50018-8

Cited by 46 publications

(65 citation statements)

References 166 publications

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“…We have corroborated the latter observations of inhibition of bone resorption by both cytochalasin D and colchicine. When the OC becomes polarized in the presence of bone, it forms three distinct membranes: a ruffled membrane, a sealing zone facing the bone substrate, and a basolateral membrane (1). Our data suggest that during this polarization, there may be an associated redistribution of NaPi to the basolateral membrane of the OC.…”

Section: Discussionmentioning

confidence: 64%

“…Osteoblasts are responsible for phosphate deposition in bone, whereas osteoclasts (OCs) 1 are involved in resorption of the mineral and matrix components of bone (1). Bone mineral is primarily hydroxyapatite, Ca 3 (PO 4 ) 2 Ca(OH) 2 , an alkaline salt, and hence its dissolution requires protonation, furnished by the proton-ATPase (H-ATPase) on the ruffled membrane of the OC (2).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, to meet the rather immense energy requirements of the OC during the cyclical processes of migration, attachment, and resorption, these cells may possess specific transport mechanisms related to Pi utilization and ATP production. The OC maintains a high demand for ATP (1,3) even when it is not secreting protons, due in part to the energy demands of motility. Several renal Na-dependent phosphate-cotransporters (NaPi) have been cloned and characterized from the rabbit and other species using the Xenopus oocyte expression cloning system (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of sodium-dependent phosphate transport in osteoclasts.

Gupta¹,

Guo²,

Alvarez³

et al. 1997

J. Clin. Invest.

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Osteoclasts are the primary cells responsible for bone resorption. They are exposed to high ambient concentrations of inorganic phosphate (Pi) during the process of bone resorption and they possess specific Pi-transport system(s) capable of taking up Pi released by bone resorption. By immunochemical studies and PCR, we confirmed previous studies suggesting the presence of an Na-dependent Pi transporter related to the renal tubular "NaPi" proteins in the osteoclast. Using polyclonal antibodies to NaPi-2 (the rat variant), an ‫ف‬ 95-kD protein was detected, localized in discrete vesicles in unpolarized osteoclasts cultured on glass coverslips. However, in polarized osteoclasts cultured on bone, immunofluorescence studies demonstrated the protein to be localized exclusively on the basolateral membrane, where it colocalizes with an Na-H exchanger but opposite to localization of the vacuolar H-ATPase. An inhibitor of phosphatidylinositol 3-kinase, wortmannin, and an inhibitor of actin cytoskeletal organization, cytochalasin D, blocked the bone-stimulated increase in Pi uptake. Phosphonoformic acid (PFA), an inhibitor of the renal NaPi-cotransporter, reduced NaPi uptake in the osteoclast. PFA also elicited a dose-dependent inhibition of bone resorption. PFA limited ATP production in osteoclasts attached to bone particles. Our results suggest that Pi transport in the osteoclast is a process critical to the resorption of bone through provision of necessary energy substrates. (

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of sodium-dependent phosphate transport in osteoclasts.

Gupta¹,

Guo²,

Alvarez³

et al. 1997

J. Clin. Invest.

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“…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)(4)(5)(6)(7).…”

mentioning

confidence: 81%

“…We failed to show PTEN association with gelsolin. 2 We then examined gelsolin association with PTP-PEST by Western blot (Fig. 4A) and immunostaining (Fig.…”

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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