Volumes of chick and rat osteoclasts cultured on glass

Piper, Kim; Boyde, A.; Jones, S. J.

doi:10.1007/bf00301607

Cited by 9 publications

(3 citation statements)

References 41 publications

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“…However, osteoclast surface was not affected by Y2 deletion, suggesting an increase in osteoclast size in these knockouts. Such a change in osteoclast morphology is consistent with an increase in resorptive activity per cell (21,22).…”

Section: Discussionsupporting

confidence: 71%

Hypothalamic Y2 receptors regulate bone formation

Baldock¹,

Sainsbury²,

Couzens³

et al. 2002

J. Clin. Invest.

112

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IntroductionGenetically obese rodents that lack leptin (ob/ob mice) or its receptor (db/db mice) show increased activity of neuropeptide Y (NPY) circuits in the hypothalamus due to lack of leptin-induced inhibition of NPY expression and secretion (1). Such increased hypothalamic NPY signaling contributes to the massive obesity, hypercorticism, stunted growth, and reproductive defects of these mice (2). Since NPY ablation in ob/ob mice attenuates all of these defects (3), these findings demonstrate that NPY is a downstream mediator of leptin's central effects.Recently it was shown that leptin can inhibit bone synthesis by action within the hypothalamus, and that mice with no or reduced leptin signaling (ob/ob, db/db, and transgenic A-ZIP/F-1 fat-deficient mice) have high bone density associated with increased bone formation (4). This effect of leptin deficiency occurred independently of increased body fat or body weight, and despite the hypercorticism, decreased somatotropic activity, and hypogonadism in ob/ob and db/db mice. Intriguingly, central infusion of NPY for 28 days in wild-type mice had the same inhibitory effect on bone function as leptin had, suggesting that the increased hypothalamic NPY expression of leptin-deficient mice does not mediate the associated increase in bone density (4). However, it is unclear from this study whether the inhibitory effects on bone of central NPY infusion are a direct consequence of hypothalamic NPY action or a secondary effect of the resulting increase in expression (5) and circulating concentrations (6) of leptin. Furthermore, NPY mediates its effects through the activation of at least five different receptors: Y1, Y2, Y4, Y5, and in the mouse also y6, all of which are expressed in the hypothalamus (7-9). The potential for simultaneous activation of all of these receptors by central NPY infusion makes it difficult to distinguish the true role of the different types of hypothalamic Y receptors in bone physiology.NPY synthesis is particularly high in neurons of the arcuate nucleus, with many of these neurons also expressing leptin receptors (10). A high percentage of these arcuate NPY-expressing neurons coexpress the Y2 receptor (11), which is thought to act as an autoreceptor that can modulate the expression and secretion of NPY and other neurotransmitters (12). Since leptin receptors and Y2 receptors are present on NPY-expressing neurons of the arcuate nucleus and are likely to share some common signaling pathways (1, 10-12), we hypothesized that the Y2 receptor might be involved in the central regulation of bone metabolism. To test this hypothesis, we generated both germline Y2 receptor knockout mice (Y2 -/- Neuropeptide Y (NPY) is a downstream modulator of leptin action, possibly at the level of the arcuate nucleus where NPY neurons are known to express both leptin receptors and Y2 receptors. In addition to the well-described role of NPY and leptin in energy balance and obesity, intracerebroventricular administration of NPY or leptin also causes bone loss. Here we sho...

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Section: Discussionsupporting

confidence: 71%

Hypothalamic Y2 receptors regulate bone formation

Baldock¹,

Sainsbury²,

Couzens³

et al. 2002

J. Clin. Invest.

112

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“…In this way, large osteoclasts can cover a larger area of bone and consequently form large resorption pits. This hypothesis is supported by data from others showing a linear correlation between the volume of chicken or rat osteoclasts and their number of nucleus (26), and by a study showing that multinucleation enhances macrophage-mediated bone resorption. Rat polykaryons in culture, derived from peritoneal stimulated and purified macrophages, showed an increased ability to bind and digest isotopic-labeled bone particles compared with mononuclear cells (27).…”

Section: Discussionsupporting

confidence: 64%

Transcriptional Activity of Nuclei in Multinucleated Osteoclasts and Its Modulation by Calcitonin

Boissy¹

2002

Endocrinology

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The function of osteoclasts is to digest the calcified bone matrix. Osteoclasts, together with myotubes, are among the rare examples of multinucleated cells found in higher vertebrates, resulting from the fusion of mononucleated progenitors belonging to the monocyte/macrophage lineage. So far, no information is available about function and transcriptional activity of multiple nuclei in osteoclasts. We have used a run-on technique to visualize RNA synthesis in individual nucleus. We provide the first evidence that nuclei of resorbing osteoclasts, isolated from chick embryo long bones, or differentiated in vitro from murine spleen cells in presence of RANKL and macrophage-colony stimulating factor, are all transcriptionally active. Nevertheless, if transcriptional activity is the same for all the nuclei within a cell, its level varies between osteoclasts: osteoclasts with highly active nuclei are always associated with resorption pits. We found that global transcription activity of resorbing osteoclasts seeded on calcified matrix is down-regulated after 5-h treatment with calcitonin, which transiently blocks resorption. This effect is reversible because calcitonin removal led to nuclear transcription activation. These results indicate a strong correlation between transcription and resorption. Finally, our data indicate that the resorption pit surface is linearly related to the nuclei number per osteoclast, strongly suggesting that functional advantage of osteoclast multinucleation is to improve resorption efficiency.

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“…There is a linear correlation between the size of the osteoclasts and the number of nucleus (50). The area of the resorption pit formed by each osteoclast can be correlated with the number of nuclei and size of the osteoclast.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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The aim of this study is to identify the exact mechanism(s) by which cytoskeletal structures are modulated during bone resorption. In this study, we have shown the possible role of different actin-binding and signaling proteins in the regulation of sealing ring formation. Our analyses have demonstrated a significant increase in cortactin and a corresponding decrease in L-plastin protein levels in osteoclasts subjected to bone resorption for 18 h in the presence of RANKL, M-CSF, and native bone particles. Time-dependent changes in the localization of L-plastin (in actin aggregates) and cortactin (in the sealing ring) suggest that these proteins may be involved in the initial and maturation phases of sealing ring formation, respectively. siRNA to cortactin inhibits this maturation process but not the formation of actin aggregates. Osteoclasts treated as above but with TNF-␣ demonstrated very similar effects as observed with RANKL. Osteoclasts treated with a neutralizing antibody to TNF-␣ displayed podosome-like structures in the entire subsurface and at the periphery of osteoclast. It is possible that TNF-␣ and RANKL-mediated signaling may play a role in the early phase of sealing ring configuration (i.e. either in the disassembly of podosomes or formation of actin aggregates). Furthermore, osteoclasts treated with alendronate or ␣v reduced the formation of the sealing ring but not actin aggregates. The present study demonstrates a novel mechanistic link between L-plastin and cortactin in sealing ring formation. These results suggest that actin aggregates formed by L-plastin independent of integrin signaling function as a core in assembling signaling molecules (integrin ␣v␤3, Src, cortactin, etc.) involved in the maturation process.Osteoclasts, the multinucleated and terminally differentiated giant cells, are involved in bone resorption. The adhesion of osteoclasts to the bone during bone resorption leads to the formation of the clear zone, an actin-rich ring-like adhesion zone circumscribing an area of bone resorption. Formation of a clear zone or sealing zone (also known as the sealing ring) has been considered to be a marker of osteoclast activation and is fundamental to the process of osteoclast bone resorption. Sealing ring formation is mediated by the dynamics of the actin cytoskeleton. Distinct pathways and signaling molecules have been shown to play roles in the organization of the sealing ring during bone resorption. Our previous observations in gelsolin null (Gsn Ϫ/Ϫ ) 2 osteoclasts demonstrated that deficiency of this protein blocks podosome assembly and motility. However, the cells still exhibit sealing ring and matrix resorption (1). Therefore, Gsn Ϫ/Ϫ osteoclasts are capable of resorbing bone, but the resorbed areas are small due to the absence of podosomes and the resulting hypomotile nature of osteoclasts (1). Observations in Gsn Ϫ/Ϫ osteoclasts also suggest that the organization of the sealing ring presumably reflect changes in the role of actinbinding proteins. Spatial configurations of actin fil...

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Volumes of chick and rat osteoclasts cultured on glass

Cited by 9 publications

References 41 publications

Hypothalamic Y2 receptors regulate bone formation

Hypothalamic Y2 receptors regulate bone formation

Transcriptional Activity of Nuclei in Multinucleated Osteoclasts and Its Modulation by Calcitonin

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

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