Acid extrusion is induced by osteoclast attachment to bone. Inhibition by alendronate and calcitonin.

Zimolo, Z.; Wesolowski, Gregg; Rodan, Gideon A.

doi:10.1172/jci118283

Cited by 108 publications

(54 citation statements)

References 45 publications

(38 reference statements)

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“…Osteoclasts from 1,25-(OH) 2 D 3 -treated cultures plated on bone or dentine slices undergo a transformation to the activated phenotype, in which actin rings form, V-ATPase is polarized to the ruffled membrane, and bone is resorbed (1,2,5). In contrast, osteoclasts from identical cultures placed on glass coverslips fail to form ruffled membranes and do not have physiologically detectable plasma membrane V-ATPase (14,15).…”

mentioning

confidence: 89%

Interaction between Vacuolar H+-ATPase and Microfilaments during Osteoclast Activation

Lee

Gluck

Holliday

1999

Journal of Biological Chemistry

112

123

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Normal bone remodeling requires precise control over the rates of bone formation by osteoblasts and degradation by osteoclasts. Bone degradation entails the activation of osteoclasts to a highly polarized state, with formation of a specialized ruffled membrane at their bone attachment site that confers the ability to resorb bone. The osteoclast ruffled membrane is bounded by a ring of actin filaments and associated proteins on the cytoplasmic face of the plasma membrane, localized to the zone on the cell surface that is adherent to bone (2-4). The adherence zone forms a tightly sealed extracellular compartment that is acidified by densely packed proton-transporting V-ATPases 1 in the ruffled membrane (1, 5); acidification of this compartment promotes dissolution of bone mineral and degradation of bone matrix protein by cysteine proteinases secreted by the osteoclast (6 -8).In osteoclasts actively resorbing bone, most of the cellular V-ATPase is polarized to the ruffled membrane (1). Polarization of V-ATPases to discrete plasmalemmal domains in epithelial cells is dependent on the microtubules in the cytoskeleton (9). The involvement of actin filaments in polarization is not yet clear, although actin filament binding to V-ATPasedense vesicles has been observed in proton-transporting epithelial cells of toad urinary bladder (10).When cultured in medium containing 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), mouse marrow cells develop into osteoclasts (11, 12) that contain most of the V-ATPase in the cultures (13). Osteoclasts from 1,25-(OH) 2 D 3 -treated cultures plated on bone or dentine slices undergo a transformation to the activated phenotype, in which actin rings form, V-ATPase is polarized to the ruffled membrane, and bone is resorbed (1, 2, 5). In contrast, osteoclasts from identical cultures placed on glass coverslips fail to form ruffled membranes and do not have physiologically detectable plasma membrane V-ATPase (14, 15).Recent studies suggest that V-ATPase is associated with the cytoskeleton in osteoclasts cultured in vitro (16, 17). V-ATPase was found in a detergent-insoluble (cytoskeletal) fraction of osteoclast-containing bone marrow cultures from normal mice (16). In contrast, in osteoclasts from osteosclerotic (oc Ϫ /oc Ϫ ) mice, which are unable to form ruffled membranes, the amount of V-ATPase in the detergent-insoluble fraction was reduced (16), prompting speculation that V-ATPase binding to the cytoskeleton might be involved in ruffled membrane formation. In addition, genetic studies from yeast point toward an association between V-ATPase and the actin cytoskeleton (18). These authors (18) postulated that alterations in the actin cytoskeleton and cytoskeletal processes caused by mutation of V-ATPase subunits are the result of indirect effects resulting, perhaps, from changes in intracellular pH affecting cytoskeletal organization.Here, we examine the interaction between the Triton-insoluble cytoskeleton and V-ATPase in mouse marrow osteoclasts. We show that V-ATPase binds actin filaments dir...

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mentioning

confidence: 89%

Interaction between Vacuolar H+-ATPase and Microfilaments during Osteoclast Activation

Lee

Gluck

Holliday

1999

Journal of Biological Chemistry

112

123

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“…We have previously shown that the sealing zone allows the passage of lowmolecular-weight markers like dextran-3000 (Stenbeck and Horton, 2000). In osteoclasts plated on glass, sealing might not be as effective as on dentine, because few acidify the subcellular space (Zimolo et al, 1995), thus allowing passage of high-molecular-weight markers, or endocytosis takes place at random sites because matrix-derived cues are missing.…”

Section: Directionality Of Endocytosis In Resorbing Osteoclastsmentioning

confidence: 99%

Endocytic trafficking in actively resorbing osteoclasts

Stenbeck

Horton

2004

Journal of Cell Science

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Endocytosis and the subsequent intracellular trafficking of the endocytosed material are important determinants of cellular function. Osteoclasts, cells of the monocyte/macrophage family, are specialized for the internalization and processing of bone matrix. Transcytosis of endocytosed material has been observed in osteoclasts but the precise mechanism controlling this process is unclear. Here, we investigate the regulation of these trafficking events. To establish the directionality and kinetics of trafficking events in resorbing osteoclasts, we devised a system using fluorescent low-molecular-weight markers as probes to follow the route taken by the digested bone matrix. We demonstrate that this route is largely distinct from the pathway followed by proteins taken up by receptor-mediated endocytosis at the basolateral plasma membrane. Endocytosis and transcytosis from the ruffled border are fast processes, with a half-life of the endocytosed material inside the cells of 22 minutes. We demonstrate the crucial role of the microtubule network in transport from the ruffled-border area and provide evidence for a role of the cytoskeleton in the overall efficacy of trafficking. Moreover, we analyse the effect of the V-ATPase inhibitor bafilomycin A1 on endocytic uptake, which gives insight into the pH-dependent regulation of membrane trafficking and resorption in osteoclasts.

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“…They act by promoting osteoclast apoptosis and inhibiting differentiation to mature osteoclasts [16,25,30,32,40,41] or by reducing osteoclast activity [2,10,11,15,31,38,40,44], either through an inhibition of farnesyl diphosphonate synthase (FPP) in the mevalonate pathway, or by otherwise inhibiting prenylation of small GTPases. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized, based primarily on studies in culture, that bisphosphonates inhibit osteoblast apoptosis [1,35,38] and may stimulate osteoblast proliferation and differentiation [18,19,23,26,41,42], leading to increased bone formation.…”

Section: Introductionmentioning

confidence: 99%

Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia

Iwata

Follet

et al. 2006

Bone

100

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Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 μg/kg/day or alendronate at 0.1, 1.0 or 10 μg/kg/day subcutaneously for 17 days to 6-month-old female Sprague-Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22-29% for risedronate, 26-36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41-50% for risedronate, 43-52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.

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Acid extrusion is induced by osteoclast attachment to bone. Inhibition by alendronate and calcitonin.

Cited by 108 publications

References 45 publications

Interaction between Vacuolar H+-ATPase and Microfilaments during Osteoclast Activation

Interaction between Vacuolar H+-ATPase and Microfilaments during Osteoclast Activation

Endocytic trafficking in actively resorbing osteoclasts

Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia

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