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

Boissy, Patrice

doi:10.1210/en.143.5.1913

Cited by 37 publications

(33 citation statements)

References 26 publications

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“…The area of the resorption pit formed by each osteoclast can be correlated with the number of nuclei and size of the osteoclast. This is because those multinucleated giant osteoclasts can cover a large area on the bone and consequently form big resorption pits (51). Big osteoclasts make multiple contacts by membrane extension and demonstrated marginal or peripheral crawling, as shown in this paper (Figs.…”

Section: Discussionsupporting

confidence: 58%

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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Section: Discussionsupporting

confidence: 58%

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

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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“…Previously, it has been shown that the resorption capacity of osteoclasts is correlated to the number of nuclei in the cells. 26 The in vitro cultures in the present study demonstrate that multinucleated cells are formed to the same extent from oc/ocϩtcirg1 cells as from WT cells. Also the number of nuclei per osteoclast did not differ between oc/ocϩtcirg1 and WT cells, indicating that the differentiation of transduced HSCs into osteoclasts was not impaired in this respect.…”

Section: Discussionsupporting

confidence: 59%

Hematopoietic stem cell–targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice

Johansson

Vries

Schoenmaker

et al. 2007

Blood

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“…(18) To explore TREM2-DAP12-mediated regulation of OC resorption, we generated mature OCs using RANKL and M-CSF, and we subsequently examined the effect of TREM2 blockade on bone resorption. TREM2 mAb treatment inhibited resorption by OC in vitro.…”

Section: Discussionmentioning

confidence: 99%

TREM2, a DAP12-Associated Receptor, Regulates Osteoclast Differentiation and Function

Humphrey

Daws

Spusta

et al. 2006

Journal of Bone and Mineral Research

143

146

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Deficiency of the signaling adapter protein DAP12 or its associated receptor TREM2 is associated with abnormal OC development in humans. Here we examine the role of TREM2 in mouse OC development and function, including migration and resorption in vitro. These results provide new evidence that TREM2 regulates OC function independent of its effects on multinucleated OC differentiation.Introduction: TREM2 (triggering receptor expressed in myeloid cells-2) associates with the signaling adapter DAP12 in osteoclasts (OCs). Genetic mutation or deletion of either the TYROBP (DAP12) or TREM2 gene is associated with the human disorder of brain and bone, Nasu-Hakola disease. We and others recently showed the critical requirement for immunoreceptor tyrosine-based activation motif (ITAM) signals through DAP12 and the Fc Receptor ␥ chain (FcR␥) during OC development. Here, we further define the role of TREM2 in OC differentiation and describe a role for TREM2 in OC migration and bone resorption. Materials and Methods:We generated monoclonal anti-mouse TREM2 antibodies (mAb), analyzed preosteoclasts and mature OCs for TREM2 surface expression, and determined the effect of antibody ligation on in vitro OC differentiation, resorption, and migration. TREM2 RNA interference (RNAi) was used to disrupt expression of TREM2 in pre-osteoclasts. Results: Using flow cytometry, our studies reveal that TREM2 is weakly expressed on C57BL/6 bone marrow macrophages (BMMs) and is upregulated during culture with RANKL and macrophage-colony stimulating factor (M-CSF). The expression of TREM2 is unaltered in DAP12-deficient OCs. Using C57BL/6 BMMs or RAW264.7 precursors, anti-TREM2 mAb treatment with RANKL and M-CSF enhances the formation of multinuclear TRACP + OCs compared with control mAb treatment. In contrast, these agents have no effect on DAP12-deficient precursors. Monoclonal Ab blockade of TREM2 on OCs generated from C57BL/6 BMMs results in decreased resorption of artificial calcium-phosphate substrate and dentine. Reduction of TREM2 expression in RAW264.7 cells by RNAi results in loss of OC formation in response to RANKL and M-CSF. Anti-TREM2 cross-linking enhances migration of C57BL/6 OCs and RAW246.7 OCs in response to M-CSF. Conclusions: Our studies indicate that the TREM2 receptor regulates OC multinucleation as well as resorption and migration of mature OCs. Thus, TREM2-DAP12 signals regulate both OC formation and function.

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

Cited by 37 publications

References 26 publications

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

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

Hematopoietic stem cell–targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice

TREM2, a DAP12-Associated Receptor, Regulates Osteoclast Differentiation and Function

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