• BMB Reports
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• 제52권8호
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• pp.514-519
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• 2019

Osteoclasts are multinucleated giant cells derived from myeloid progenitors. Excessive bone resorption by osteoclasts can result in serious clinical outcomes for which better treatment options are needed. Here, we identified fibronectin leucine-rich transmembrane protein 2 (Flrt2), a ligand of the Unc5 receptor family for neurons, as a novel target associated with the late/maturation stage of osteoclast differentiation. Flrt2 expression is induced by stimulation with receptor activator of nuclear factor-kB ligand (RANKL). Flrt2 deficiency in osteoclasts results in reduced hyper-multinucleation, which could be restored by RNAi-mediated knockdown of Unc5b. Treatment with Netrin1, another ligand of Unc5b which negatively controls osteoclast multinucleation through down regulation of RANKL-induced Rac1 activation, showed no inhibitory effects on Flrt2-deficient cells. In addition, RANKL-induced Rac1 activation was attenuated in Flrt2-deficient cells. Taken together, these results suggest that Flrt2 regulates osteoclast multinucleation by interfering with Netrin 1-Unc5b interaction and may be a suitable therapeutic target for diseases associated with bone remodeling.

• BMB Reports
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• 제53권9호
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• pp.472-477
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• 2020

Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-κB ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induced by RANKL stimulation, and that RNAi-mediated knockdown of Pcdh7 resulted in impaired formation of osteoclasts. We generated Pcdh7-deficient mice and found increased bone mass due to decreased bone resorption but without any defect in bone formation. Using an in vitro culture system, it was revealed that formation of multinucleated osteoclasts is impaired in Pcdh7-deficient cultures, while no apparent defects were observed in differentiation and function of Pcdh7-deficient osteoblasts. Taken together, these results reveal an osteoclast cell-intrinsic role for Pcdh7 in maintaining bone homeostasis.

• Journal of Microbiology and Biotechnology
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• 제11권5호
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• pp.727-738
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• 2001

Macrophagal polykaryocytes (MPs) are terminally differentiated multinuclear macrophage cells responsible for remodeling and resorption of bone, foreign body, and tissue deposition in inflammation. MPs are encountered only in bone and cartilagenous tissues, in which they are referred to as osteoclasts, odontoclasts, in which they are referred to as osteoclasts, odontoclasts, and septoclasts. Depending on the disease, the MPs differentiate into many morphological variants that include foreign-body giant cells, Langhans-type cells, and Touton-type cells. Morphological heterogeneity of MPs could Touton-type cells. Morphological heterogeneity of MPs could reflect the giant cell formation from phenotypically different marophage precursors by the process of fusion. At present, many cytokines, adhesion/fusion molecules, and other factors of the microenvironment have been discovered that influence the multinucleation process. Many evidences suggest that conditions in giant cell fibrohistiocytomas, which facilitate MP formation, are similar to the inflammation site of granulomatosis. MPs in the giant cell tumors and granulomatosis foci are formed in response to the factors secreted by mesenchymal cells. It is proposed that one of the first steps in vertebrate evolution could be the organization of skeleton remodeling, in which osteoclasts play a major role. In this step, the same mechanism of regulations served as a basis for the development of both osteoclast and inflammatory forms of MPs.

• Journal of Korean Dental Science
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• 제8권2호
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• pp.74-81
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• 2015

Purpose: In osteoclast differentiation, actin-rich membrane protrusions play a crucial role in cell adhesion. Odontogenic ameloblast-associated protein (Odam) contributes to cell adhesion by inducing actin rearrangement. Odam-mediated RhoA activity may play a significant role in multinucleation of osteoclasts. However, the precise function of Odam in osteoclast cell adhesion and differentiation remains largely unknown. Here, we identify a critical role for Odam in inducing osteoclast adhesion and differentiation. Materials and Methods: The expression of Odam in osteoclasts was evaluated by immunohistochemistry. Primary mouse bone marrow and RAW264.7 cells were used to test the cell adhesion and actin ring formation induced by Odam. Result: Odam was expressed in osteoclasts around alveolar bone. Odam transfection induced actin filament rearrangement and cell adhesion compared with the control or collagen groups. Overexpression of Odam promoted actin stress fiber remodeling and cell adhesion, resulting in increased osteoclast fusion. Conclusion: These results suggest that Odam expression in primary mouse osteoclasts and RAW264.7 cells promotes their adhesion, resulting in the induction of osteoclast differentiation.

• 대한세포병리학회지
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• 제8권1호
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• pp.1-10
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• 1997

The fine needle aspiration biopsy(FNAB) has become a popular method to diagnose mass lesions of the liver. Although many reports have listed FNAB criteria to be used to diagnose hepatocellular carcinoma(HCC), a diagnostic dilemma still exists at the extreme ends of the spectrum, particularly for well differentiated HCC. The authors reviewed a series of FNAB specimens of the liver to distinguish well differentiated HCC from nonneoplastic liver. Fifteen cytologic features were examined in this study: high cellularity, large sheet formation, trabecular pattern, acinar pattern, dispersed pattern, irregular arrangement, increased nuclear/cytoplasmic ratio, naked nuclei, irregular chromatin, irregular nuclear contour, multinucleation, uniform macronucleoli, multiple nuclei, uniform small cytoplasm and monotony of atypia. These features were examined in a series of 76 FNAB specimens. Fifty two specimens were from patients with HCC and 24 specimens were from patients with nonneoplastic lesion or tumors other than HCC containg adequate amount of nonneoplastic hepatocytes in smear. All specimens were coded as to the presence or absence of the above cytologic features. With the use of step-wise logistic regression analysis, three features were identified as the key cytologic features predictive of HCC: irregular chromatin, monotony of atypia and absence of large sheet formation. When these criteria were used, the sensitivity diagnosing HCC by FNAB was 94.2%, specificity 100%, positive predictive value 100% and negative predictive value was 88.9%.

• Clinical and Experimental Reproductive Medicine
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• 제45권1호
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• pp.52-55
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• 2018

This study retrospectively assessed whether time-lapse data relating to developmental timing and morphology were associated with clinical outcomes, with the eventual goal of using morphokinetic variables to select embryos prospectively for cryopreservation. In this study, we examined the clinical outcomes of single vitrified-warmed blastocyst transfer cycles that were cultured in a time-lapse incubation system. The morphokinetic variables included uneven pronuclei, an uneven blastomere, multinucleation, and direct, rapid, and irregular division. A total of 164 single vitrified-warmed blastocyst transfer cycles were analyzed (102 cycles of regularly developed blastocysts and 62 cycles of blastocysts with morphokinetic variables). No significant differences in the age of females or the standard blastocyst morphology were found between these two groups. The regularly developed blastocysts showed significantly higher implantation and clinical pregnancy rates than the blastocysts exhibiting morphokinetic variables (30.4% vs. 9.7% and 37.3% vs. 14.5%, respectively; p< 0.01). The blastocysts that exhibited morphokinetic variables showed different mean development times compared with the regularly developed blastocysts. Although morphokinetic variables are known to have fatal impacts on embryonic development, a considerable number of embryos developed to the blastocyst stage. Morphokinetic variables had negative effects on the implantation and clinical pregnancy rates in vitrified-warmed blastocyst transfer cycles. These findings suggest that blastocysts cultured in a time-lapse incubation system should be considered for selective cryopreservation according to morphokinetic variables.