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- 저자 : Takegahara, N. (검색결과 5 건)
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Kang, Sujin,Okuno, Tatsusada,Takegahara, Noriko,Takamatsu, Hyota,Nojima, Satoshi,Kimura, Tetsuya,Yoshida, Yuji,Ito, Daisuke,Ohmae, Saori,You, Dong-Ju,Toyofuku, Toshihiko,Jang, Myoung Ho,Kumanogoh, Ats Williams Wilkins 2012 JOURNAL OF IMMUNOLOGY Vol.188 No.3
<P>The intestinal immune system is constantly challenged by commensal bacteria; therefore, it must maintain quiescence via several regulatory mechanisms. Although intestinal macrophages (Ms) have been implicated in repression of excessive inflammation, it remains unclear how their functions are regulated during inflammation. In this study, we report that semaphorin 7A (Sema7A), a GPI-anchored semaphorin expressed in intestinal epithelial cells (IECs), induces IL-10 production by intestinal M?s to regulate intestinal inflammation. Sema7A-deficient mice showed severe signs of dextran sodium sulfate-induced colitis due to reduced intestinal IL-10 levels. We further identified CX3CR1(+)MHC class II(int)F4/80(hi)CD11b(hi) M?s as the main producers of IL-10 via αvβ1 integrin in response to Sema7A. Notably, Sema7A was predominantly expressed on the basolateral side of IECs, and its expression pattern was responsible for protective effects against dextran sodium sulfate-induced colitis and IL-10 production by M?s during interactions between IECs and M?s. Furthermore, we determined that the administration of recombinant Sema7A proteins ameliorated the severity of colitis, and these effects were diminished by IL-10-blocking Abs. Therefore, our findings not only indicate that Sema7A plays crucial roles in suppressing intestinal inflammation through αvβ1 integrin, but also provide a novel mode of IL-10 induction via interactions between IECs and M?s.</P>
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Flrt2 is involved in fine-tuning of osteoclast multinucleation
( Jumpei Shirakawa ),( Noriko Takegahara ),( Hyunsoo Kim ),( Seoung Hoon Lee ),( Kohji Sato ),( Satoru Yamagishi ),( Yongwon Choi ) 생화학분자생물학회 2019 BMB Reports Vol.52 No.8
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, RANKLinduced 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 2019; 52(8): 514-519]
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Hyunsoo Kim,Noriko Takegahara,Matthew C. Walsh,Jun Ueda,Yoshitaka Fujihara,Masahito Ikawa,Yongwon Choi 생화학분자생물학회 2020 BMB Reports Vol.53 No.9
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-B 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.
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Tmem64 Modulates Calcium Signaling during RANKL-Mediated Osteoclast Differentiation
Kim, H.,Kim, T.,Jeong, B.C.,Cho, I.T.,Han, D.,Takegahara, N.,Negishi-Koga, T.,Takayanagi, H.,Lee, J.,Sul, J.Y.,Prasad, V.,Lee, S.,Choi, Y. Cell Press 2013 Cell metabolism Vol.17 No.2
Osteoclast maturation and function primarily depend on receptor activator of NF-κB ligand (RANKL)-mediated induction of nuclear factor of activated T cells c1 (NFATc1), which is further activated via increased intracellular calcium ([Ca<SUP>2+</SUP>]<SUB>i</SUB>) oscillation. However, the coordination mechanism that mediates Ca<SUP>2+</SUP> oscillation during osteoclastogenesis remains ill defined. Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca<SUP>2+</SUP> oscillation during osteoclastogenesis. We found that Tmem64-deficient mice exhibit increased bone mass due in part to impaired osteoclast formation. Using in vitro osteoclast culture systems, we show here that Tmem64 interacts with sarcoplasmic endoplasmic reticulum Ca<SUP>2+</SUP> ATPase 2 (SERCA2) and modulates its activity. Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca<SUP>2+</SUP>]<SUB>i</SUB> oscillation, which results in reduced Ca<SUP>2+</SUP>/calmodulin-dependent protein kinases (CaMK) IV and mitochondrial ROS, both of which contribute to achieving the CREB activity necessary for osteoclast formation. These data demonstrate that Tmem64 is a positive modulator of osteoclast differentiation via SERCA2-dependent Ca<SUP>2+</SUP> signaling.
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The purinergic receptor P2X5 contributes to bone loss in experimental periodontitis
( Hyunsoo Kim ),( Tetsuhiro Kajikawa ),( Matthew C. Walsh ),( Noriko Takegahara ),( Yun Hee Jeong ),( George Hajishengallis ),( Yongwon Choi ) 생화학분자생물학회 2018 BMB Reports Vol.51 No.9
Purinergic receptor signaling is increasingly recognized as an important regulator of inflammation. The P2X family purinergic receptors P2X5 and P2X7 have both been implicated in bone biology, and it has been suggested recently that P2X5 may be a significant regulator of inflammatory bone loss. However, a role for P2X5 in periodontitis is unknown. The present study aimed to evaluate the functional role of P2X5 in ligatureinduced periodontitis in mice. Five days after placement of ligature, analysis of alveolar bone revealed decreased bone loss in P2rx5<sup>-/-</sup> mice compared to P2rx7<sup>-/-</sup> and WT control mice. Gene expression analysis of the gingival tissue of ligated mice showed that IL1b, IL6, IL17a and Tnfsf11 expression levels were significantly reduced in P2rx5<sup>-/-</sup> compared to WT mice. These results suggest the P2X5 receptor may regulate bone loss related to periodontitis and it may thus be a novel therapeutic target in this oral disease. [BMB Reports 2018; 51(9): 468-473]
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