Studies of OC-STAMP in Osteoclast Fusion: A New Knockout Mouse Model, Rescue of Cell Fusion, and Transmembrane Topology

Witwicka, Hanna; Hwang, Sung-Yong; Reyes-Gutierrez, Pablo; Ji, Hong; Odgren, Paul E.; Donahue, Leah Rae; Birnbaum, Mark J.; Odgren, Paul R.

doi:10.1371/journal.pone.0128275

Cited by 64 publications

(65 citation statements)

References 31 publications

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“…In addition to DC‐STAMP, OC‐STAMP is another critical RANKL‐induced, multipass transmembrane protein that promotes the formation and differentiation of osteoclasts (Yang et al, ; Witwicka et al, ). In addition to their structure similarity, DC‐STAMP and OC‐STAMP share many common features.…”

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

“…Whether OC‐STAMP glycosylation will affect DC‐STAMP surface expression or function remains to be investigated by using, the available mutated glycosylation‐deficient (N162D) OC‐STAMP (Witwicka et al, ). Based on the structural similarity between DC‐STAMP and OC‐STAMP and current topology analysis by the TMHMM algorithm (Witwicka et al, ), it will be interesting to investigate whether DC‐STAMP is a 7‐pass transmembrane protein as originally considered (Yagi et al, ). According to a recent review and two studies on OC‐STAMP (Yang et al, ; Zhang et al, ; Witwicka et al, ), the topology of DC‐STAMP (whether it is a 5, 6, or 7‐pass transmembrane protein) remains an open question which needs further investigation to determine its similarity to OC‐STAMP, a 6‐pass transmembrane protein.…”

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

“…Based on the structural similarity between DC‐STAMP and OC‐STAMP and current topology analysis by the TMHMM algorithm (Witwicka et al, ), it will be interesting to investigate whether DC‐STAMP is a 7‐pass transmembrane protein as originally considered (Yagi et al, ). According to a recent review and two studies on OC‐STAMP (Yang et al, ; Zhang et al, ; Witwicka et al, ), the topology of DC‐STAMP (whether it is a 5, 6, or 7‐pass transmembrane protein) remains an open question which needs further investigation to determine its similarity to OC‐STAMP, a 6‐pass transmembrane protein. To date, these two STAMPs are the only cell‐type specific proteins essential for cell–cell fusion and the generation of osteoclasts and giant cells, making their role in osteoclastogenesis and macrophage fusion (Miyamoto et al, ) of particular interest and importance.…”

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

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DC-STAMP: A Key Regulator in Osteoclast Differentiation

Chiu

Ritchlin

2016

J. Cell. Physiol.

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Osteoimmunology research is a new emerging research field that investigates the links between the bone and immune responses. Results from osteoimmunology studies suggest that bone is not only an essential component of the musculoskeletal system, but is also actively involved in immune regulation. Many important factors involved in immune regulation also participate in bone homeostasis. Bone homeostasis is achieved by a coordinated action between bone synthesizing osteoblasts and bone degrading osteoclasts. An imbalanced action between osteoblasts and osteoclasts often results in pathological bone diseases: osteoporosis is caused by an excessive osteoclast activity, whereas osteopetrosis results from an increased osteoblast activity. This review focuses on dendritic cell specific transmembrane protein (DC STAMP), an important protein currently considered as a master regulator of osteoclastogenesis. Of clinical relevance, the frequency of circulating DC STAMPþ cells is elevated during the pathogenesis of psoriatic diseases. Intriguingly, recent results suggest that DC STAMP also plays an imperative role in bone homeostasis by regulating the differentiation of both osteoclasts and osteoblasts. This article summarizes our current knowledge on DC STAMP by focusing on its interacting proteins, its regulation on osteoclastogenesis related genes, its possible involvement in immunoreceptor tyrosine based inhibitory motif (ITIM) mediated signaling cascade, and its potential of developing therapeutics for clinical applications.

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Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

Section: Updates On Dc‐stamp Researchmentioning

confidence: 99%

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DC-STAMP: A Key Regulator in Osteoclast Differentiation

Chiu

Ritchlin

2016

J. Cell. Physiol.

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“…cell-cell fusion. In particular, dendritic cell-specific transmembrane protein (DC-STAMP) (2), OC-stimulatory transmembrane protein (OC-STAMP) (3)(4)(5), and CD9 (6,7) are all reported to play essential roles in OC fusion.…”

mentioning

confidence: 99%

OC‐STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up‐regulation of permissive fusogen CD9

Ishii

Ruiz-Torruella²,

Ikeda³

et al. 2018

FASEB j.

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Cell fusion-mediated formation of multinuclear osteoclasts (OCs) plays a key role in bone resorption. It is reported that 2 unique OC-specific fusogens [ i.e., OC-stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP)], and permissive fusogen CD9, are involved in OC fusion. In contrast to DC-STAMP-knockout (KO) mice, which show the osteopetrotic phenotype, OC-STAMP-KO mice show no difference in systemic bone mineral density. Nonetheless, according to the ligature-induced periodontitis model, significantly lower level of bone resorption was found in OC-STAMP-KO mice compared to WT mice. Anti-OC-STAMP-neutralizing mAb down-modulated in vitro: 1) the emergence of large multinuclear tartrate-resistant acid phosphatase-positive cells, 2) pit formation, and 3) mRNA and protein expression of CD9, but not DC-STAMP, in receptor activator of NF-κB ligand (RANKL)-stimulated OC precursor cells (OCps). While anti-DC-STAMP-mAb also down-regulated RANKL-induced osteoclastogenesis in vitro, it had no effect on CD9 expression. In our mouse model, systemic administration of anti-OC-STAMP-mAb suppressed the expression of CD9 mRNA, but not DC-STAMP mRNA, in periodontal tissue, along with diminished alveolar bone loss and reduced emergence of CD9 OCps and tartrate-resistant acid phosphatase-positive multinuclear OCs. The present study demonstrated that OC-STAMP partners CD9 to promote periodontal bone destruction by up-regulation of fusion during osteoclastogenesis, suggesting that anti-OC-STAMP-mAb may lead to the development of a novel therapeutic regimen for periodontitis.-Ishii, T., Ruiz-Torruella, M., Ikeda, A., Shindo, S., Movila, A., Mawardi, H., Albassam, A., Kayal, R. A., Al-Dharrab, A. A., Egashira, K., Wisitrasameewong, W., Yamamoto, K., Mira, A. I., Sueishi, K., Han, X., Taubman, M. A., Miyamoto, T., Kawai, T. OC-STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up-regulation of permissive fusogen CD9.

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Conditional Disruption of miR17∼92 in Osteoclasts Led to Activation of Osteoclasts and Loss of Trabecular Bone in Part Through Suppression of the miR17‐Mediated Downregulation of Protein‐Tyrosine Phosphatase‐oc in Mice

et al. 2017

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This study sought to understand the regulation of an osteoclastic protein-tyrosine phosphatase (PTP-oc), a positive regulator of osteoclast activaty. Our past studies suggested that PTP-oc is regulated post-transcriptionally. The 3’-UTR of PTP-oc mRNA contains a target site for miR17. During osteoclastic differentiation, there was an inverse relationship between the cellular levels of miR17 (expressed as one of the six cluster genes of miR17~92) and PTP-oc mRNA. Overexpression of pre-miR17~92 in mouse osteoclast precursors reduced PTP-oc mRNA level and the size of the derived osteoclasts; whereas deletion of miR17~92 or inhibition of miR17 resulted in the formation of larger osteoclasts containing more nuclei that expressed higher PTP-oc mRNA levels and created larger resorption pits. Thus, PTP-oc-mediated osteoclast activation is modulated in part by miR17~92, particularly miR17. The miR17~92 osteoclast conditional knockout (cKO) mutants, generated by breeding miR17~92loxp/loxp mice with Ctsk-Cre mice, had lower Tb.BV/TV, Tb.BMD, Tb.Conn-Dens, Tb.N, and Tb.Th, but larger Tb.Sp, and greater bone resorption without a change in bone formation compared to littermate controls. The cKO marrow-derived osteoclasts were twice as large, contained twice as many nuclei, and produced twice as large resorption pits as osteoclasts of littermate controls. The expression of genes associated with osteoclast activation was increased in cKO osteoclasts, suggesting that deletion of miR17~92 in osteoclasts promotes osteoclast activation. The cKO osteoblasts did not show differences in cellular miR17 level, alkaline phosphatase activity, and bone nodule formation ability. In conclusion, miR17-92 negatively regulates the osteoclast activity, in part via the miR17-mediated suppression of PTP-oc in osteoclasts.

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Studies of OC-STAMP in Osteoclast Fusion: A New Knockout Mouse Model, Rescue of Cell Fusion, and Transmembrane Topology

Cited by 64 publications

References 31 publications

DC-STAMP: A Key Regulator in Osteoclast Differentiation

DC-STAMP: A Key Regulator in Osteoclast Differentiation

OC‐STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up‐regulation of permissive fusogen CD9

Conditional Disruption of miR17∼92 in Osteoclasts Led to Activation of Osteoclasts and Loss of Trabecular Bone in Part Through Suppression of the miR17‐Mediated Downregulation of Protein‐Tyrosine Phosphatase‐oc in Mice

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