記述言語：英語   出版者・発行元：Discover Oncology  

Objectives: Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses anticancer and antiangiogenic effects in some malignant tumors. Therefore, we investigated the anticancer and antiangiogenic effects of LEF on oral squamous cell carcinoma (OSCC). Methods: To evaluate the inhibitory effect of LEF on OSCC, cell proliferation and wound-healing assays using human OSCC cell lines were performed. The DHODH inhibitory effect of LEF was evaluated by Western blot. To assess the suppression of pyrimidine biosynthesis induced by LEF on OSCC, cell proliferation assays with or without uridine supplementation were performed. The antiangiogenic effect of LEF was evaluated by in vitro tube formation assay using immortalized human umbilical vein endothelial cells, which were electroporatically transfected with hTERT. The tumor-suppressive effect of LEF in vivo was examined in both immunodeficient and syngeneic mice by implanting mouse OSCC cells. Tumor vascularization was evaluated by immunohistochemistry of the tumor extracted from syngeneic mice. Results: LEF dose-dependently inhibited OSCC proliferation and migration. LEF significantly inhibited DHODH expression, and uridine supplementation rescued the inhibitory effect of LEF. LEF dose-dependently suppressed endothelial tube formation. In the animal study, LEF significantly suppressed tumor growth in both immunodeficient and syngeneic mice. Histologically, LEF decreased DHODH expression and tumor vascularization. Conclusion: LEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning.

DOI： 10.1007/s12672-025-01763-5

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記述言語：英語   出版者・発行元：Inflammation  

Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammatory diseases and immune responses. Recently, a novel transcriptional regulatory mechanism of NF-κB involving the phosphorylation of serine 536 (534 in mice; S534) of its p65 subunit was reported; however, further research is required to elucidate the physiological role of S534 phosphorylation. Therefore, we generated S534A knock-in (KI) mice, in which the S534 of p65 was substituted with alanine. Similar to the wild-type (WT) mice, S534A KI mice developed normally. After stimulation with tumor necrosis factor α (TNFα), mouse embryonic fibroblasts (MEFs) derived from S534A KI mice exhibited increased target gene expression compared with that in the WT MEFs, which was induced by long-term binding of p65 to DNA. According to comprehensive gene expression analysis after stimulation with TNFα, the expression of genes p65ted to inflammatory and immune responses was increased, and the expression of genes p65ted to lipolysis was decreased in S534A KI MEFs. Analyses of a periodontal disease model established using WT and S534A KI mice revealed that alveolar bone resorption was enhanced in S534A KI mice owing to an increase in the number of osteoclasts, which was not attributed to the differentiation of osteoclast precursor cells but to an increased expression of interleukin-1β and receptor activator of NF-κB ligand in the periodontal tissue. Hence, phosphorylation of S536 negatively regulates inflammatory responses in vitro and in vivo.

DOI： 10.1007/s10753-024-02140-0

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記述言語：英語   出版者・発行元：Biochemical and Biophysical Research Communications  

Nuclear factor (NF)-κB signaling is not only important for the immune and inflammatory responses but also for the normal development of epithelial cells, such as those in the skin and tooth. Here, we generated epithelial cell-specific p65-deficient (p65Δepi−/−) mice to analyze the roles of NF-κB signaling in epithelial cell developent. Notably, p65Δepi−/− mice exhibited no abnormalities in their appearance compared to the control (p65flox/flox) littermates. Furthermore, no major changes were observed in the skin, hair growth, and shape and color of the incisors and molars. However, 65 % of p65Δepi−/− mice exhibited corneal thickening after 8 weeks of age, and 30 % of p65Δepi−/− mice exhibited hair growth from the mandibular incisors around 24 weeks of age. No hair growth was observed at 36 and 42 weeks of age. However, micro-computed tomography images revealed a large cavity below the mandibular incisors extending to the root of the incisor. Histological analysis revealed that the cavity was occupied by a connective tissue containing hair-like structures with many dark brown granules that disappeared after melanin bleaching, confirming the presence of hair. Although inflammatory cells were also observed near the eruption site of the incisor teeth of p65Δepi−/− mice, no major disturbance was observed in the arrangement of enamel epithelial cells. Overall, these results highlight the role of p65 in the maintenance of epithelial cell homeostasis during aging.

DOI： 10.1016/j.bbrc.2024.150143

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1016/j.bbrc.2022.09.065.

リポジトリ公開URL： https://hdl.handle.net/2324/7178663

記述言語：英語   出版者・発行元：FEBS Letters  

GPRC5C is an orphan G protein-coupled receptor (GPCR) that belongs to the class C GPCR family. Although GPRC5C is expressed in various organs, its function and ligand are still undetermined. We found that GPRC5C is expressed in mouse taste cells, enterocytes, and pancreatic α-cells. In functional imaging assays, HEK293 cells heterologously expressing GPRC5C and the chimeric G protein α subunit Gα16-gust44 showed robust intracellular Ca2+ increases in response to monosaccharides, disaccharides, and a sugar alcohol, but not an artificial sweetener or sweet-tasting amino acid. Notably, Ca2+ increases occurred after washout, not during stimulation. Our findings suggest that GPRC5C has receptor properties which lead to novel ‘off’ responses to saccharide detachment and may work as an internal or external chemosensor specifically tuned to natural sugars.

DOI： 10.1002/1873-3468.14695

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記述言語：英語   出版者・発行元：Development (Cambridge)  

Endochondral ossification contributes to longitudinal skeletal growth. Osteoblasts, which are bone-forming cells, appear close to terminally differentiated hypertrophic chondrocytes during endochondral ossification. We established mice with conditional knockout (cKO) of Smad4, an essential co-activator for transforming growth factor β family signaling. The mice showed a marked increase in bone volume in the metaphysis as a result of increased bone formation by osteoblasts, in which β-catenin, an effector of canonical Wnt signaling, accumulated. We identified Wnt7b as a factor with increased expression in growth plate cartilage in Smad4 cKO mice. Wnt7b mRNA was expressed in differentiated chondrocytes and suppressed by BMP4 stimulation. Ablation of Wnt7b blunted the increase in bone in adult Smad4 cKO mice and reduced skeletal growth in juvenile mice. Overall, we conclude that Wnt7b is a crucial factor secreted from hypertrophic chondrocytes to initiate endochondral ossification. These results suggest that Smad4-dependent BMP signaling regulates the Wnt7b–β-catenin axis during endochondral ossification.

DOI： 10.1242/dev.201734

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記述言語：英語   出版者・発行元：Frontiers in Immunology  

Periodontal disease is an infectious disease that affects many people worldwide. Disease progression destroys the alveolar bone and causes tooth loss. We have previously shown that alymphoplasia (aly/aly) mice harboring a loss-of-function mutation in the map3k14 gene, which is involved in p100 to p52 processing of the alternative NF-κB pathway, exhibited mild osteopetrosis due to decreased number of osteoclasts, suggesting the alternative NF-κB pathway as a potential drug target for the amelioration of bone disease. In the present study, wild-type (WT) and aly/aly mice were subjected to silk ligation to establish a periodontitis model. Alveolar bone resorption was suppressed in aly/aly mice by decreased numbers of osteoclasts in the alveolar bone in comparison to WT mice. Furthermore, the expression of receptor activator of NF-κB ligand (RANKL) and TNFα (cytokines involved in osteoclast induction in periligative gingival tissue) was decreased. When primary osteoblasts (POBs) and bone marrow cells (BMCs) derived from WT and aly/aly mice were prepared and co-cultured, osteoclasts were induced from WT-derived BMCs, regardless of the origin of the POBs, but hardly formed from aly/aly mouse-derived BMCs. Furthermore, the local administration of an NIK inhibitor, Cpd33, inhibited osteoclast formation and thereby inhibited alveolar bone resorption in the periodontitis model. Therefore, the NIK-mediated NF-κB alternative pathway can be a therapeutic target for periodontal disease.

DOI： 10.3389/fimmu.2023.1179007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-023-32390-1.

リポジトリ公開URL： https://hdl.handle.net/2324/7178662

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbamcr.2022.119404.

記述言語：英語   出版者・発行元：International Journal of Molecular Sciences  

The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis.

DOI： 10.3390/ijms23147995

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1530/JOE-21-0424

リポジトリ公開URL： https://hdl.handle.net/2324/7178665

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1242/jcs.258584.

記述言語：英語   出版者・発行元：Journal of Pathology  

Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF–MAPK pathway and Wnt/β-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS–MAPK pathway and Wnt/β-catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1–MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1–ARL4C and BRAFV600E–MEK/ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1–MEK/ERK–ARL4C axis, which may function in cooperation with the BRAFV600E–MEK/ERK pathway, promotes ameloblastoma development. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.5814

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記述言語：日本語   出版者・発行元：一般社団法人 日本DOHaD学会  

DOI： 10.51067/dohad.10.2_42

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bone.2021.116210

リポジトリ公開URL： https://hdl.handle.net/2324/7178667

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41374-021-00661-y.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.molmet.2021.101360.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/path.5814.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejphar.2021.173881.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1016/j.jbc.2021.100274.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pro-inflammatory cytokines prevent bone regeneration in vivo and activation of nuclear factor-κB (NF-κB) signaling has been proposed to lead to suppression of bone morphogenetic protein (BMP)-induced osteogenesis via direct binding of p65 to Smad4 in vitro. Application of a small nuclear acidic protein (MTI-II) and its delivered peptide, MPAID (MTI-II peptide anti-inflammatory drug) has been described to elicit therapeutic potential via strong anti-inflammatory action following the physical association of MTI-II and MPAID with p65. However, it is unclear whether MTI-II attenuates tumor necrosis factor (TNF)-α inhibition of BMP-induced osteogenesis. Herein, we found that TNF-α-mediated suppression of responses associated with BMP4-induced osteogenesis, including expression of the osteocalcin encoding gene Ocn, Smad binding element (SBE)-dependent luciferase activity, alkaline phosphatase activity, and alizarin red S staining were largely restored by MTI-II and MPAID in MC3T3-E1 cells. Mechanistically, MTI-II and MPAID did not inhibit nuclear translocation of p65 or disassociate Smad4 from p65. Further, results from chromatin immunoprecipitation (ChIP) analyses revealed that Smad4 enrichment in cells over-expressing MTI-II and treated with TNF-α was equivalent to that in cells without TNF-α treatment. Alternatively, Smad4 enrichment was considerably decreased following TNF-α treatment in control cells. Moreover, p65 enrichment in the Id-1 promoter SBE was detected only when cells over-expressing MTI-II were stimulated with TNF-α. Overall, our study concludes that MTI-II restored TNF-α-inhibited suppression of BMP-Smad-induced osteogenic differentiation by enhancing accessibility of the Smad4-p65 complex to the SBE rather than by liberating Smad4 from p65.

DOI： doi: 10.1007/s11010-020-03734-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Musculoskeletal diseases and disorders, including osteoporosis and rheumatoid arthritis are diseases that threaten a healthy life expectancy, and in order to extend the healthy life expectancy of elderly people, it is important to prevent bone and joint diseases and disorders. We previously reported that alymphoplasia (aly/aly) mice, which have a loss-of-function mutation in the Nik gene involved in the processing of p100 to p52 in the alternative NF-κB pathway, show mild osteopetrosis with a decrease in the osteoclast number, suggesting that the alternative NF-κB pathway is a potential drug target for ameliorating bone diseases. Recently, the novel NF-κB-inducing kinase (NIK)-specific inhibitor compound 33 (Cpd33) was developed, and we examined its effect on osteoclastic bone resorption in vitro and in vivo. Cpd33 inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis accompanied by a decrease in the expression of nfatc1, dc-stamp, and cathepsin K, markers of osteoclast differentiation, without affecting the cell viability, in a dose-dependent manner. Cdp33 specifically suppressed the RANKL-induced processing of p100 to p52 but not the phosphorylation of p65 or the degradation or resynthesis of IκBα in osteoclast precursors. Cpd33 also suppressed the bone-resorbing activity in mature osteoclasts. Furthermore, Cdp33 treatment prevented bone loss by suppressing the osteoclast formation without affecting the osteoblastic bone formation in ovariectomized mice. Taken together, NIK inhibitors may be a new option for patients with a reduced response to conventional pharmacotherapy or who have serious side effects.

DOI： doi: 10.1016/j.bone.2020.115316.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bone invasion is a critical factor in determining the prognosis of oral squamous cell carcinoma (OSCC) patients. Transforming growth factor β (TGF-β) is abundantly expressed in the bone matrix and is involved in the acquisition of aggressiveness by tumors. TGF-β) is also important to cytoskeletal changes during tumor progression. In this study, we examined the relationship between TGF-β signaling and cytoskeletal changes during bone invasion by OSCC. Immunohistochemical staining of OSCC samples from 5 patients showed the expression of p130Cas (Crk-associated substrate) in the cytoplasm and phosphorylated Smad3 expression in the nucleus in OSCC cells. TGF-β1 induced the phosphorylation of Smad3 and p130Cas as well as epithelial-mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherin, a marker of epithelial cells, and the upregulation of the expression of N-cadherin, or Snail, a marker of mesenchymal cells, in human HSC-2 cells and mouse SCCVII cells. SB431542, a specific inhibitor of Smad2/3 signaling, abrogated the TGF-β1-induced phosphorylation of p130Cas and morphological changes. Silencing p130Cas using an shRNA or siRNA in SCCVII cells suppressed TGF-β1-induced cell migration, invasion, EMT, and matrix metalloproteinase-9 (MMP-9) production. Compared with control SCCVII cells, SCCVII cells with silenced p130Cas strongly suppressed zygomatic and mandibular destruction in vivo by reducing the number of osteoclasts, cell proliferation and MMP-9 production. Taken together, these results showed the expression of TGF-β/p130Cas might be a new target for the treatment of OSCC bone invasion

DOI： 10.1093/carcin/bgaa007.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Podosome formation in osteoclasts is an important initial step in osteoclastic bone resorption. Mice lacking c-Src (c-Src-/- ) exhibited osteopetrosis due to a lack of podosome formation in osteoclasts. We previously identified p130Cas (Crk-associated substrate [Cas]) as one of c-Src downstream molecule and osteoclast-specific p130Cas-deficient (p130CasΔOCL-/- ) mice also exhibited a similar phenotype to c-Src-/- mice, indicating that the c-Src/p130Cas plays an important role for bone resorption by osteoclasts. In this study, we performed a cDNA microarray and compared the gene profiles of osteoclasts from c-Src-/- or p130CasΔOCL-/- mice with wild-type (WT) osteoclasts to identify downstream molecules of c-Src/p130Cas involved in bone resorption. Among several genes that were commonly downregulated in both c-Src-/- and p130CasΔOCL-/- osteoclasts, we identified kinesin family protein 1c (Kif1c), which regulates the cytoskeletal organization. Reduced Kif1c expression was observed in both c-Src-/- and p130CasΔOCL-/- osteoclasts compared with WT osteoclasts. Kif1c exhibited a broad tissue distribution, including osteoclasts. Knockdown of Kif1c expression using shRNAs in WT osteoclasts suppressed actin ring formation. Kif1c overexpression restored bone resorption subsequent to actin ring formation in p130CasΔOCL-/- osteoclasts but not c-Src-/- osteoclasts, suggesting that Kif1c regulates osteoclastic bone resorption in the downstream of p130Cas.

DOI： doi: 10.1002/cbf.3476.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Skeletal tissue homeostasis is maintained via the balance of osteoclastic bone resorption and osteoblastic bone formation. Autophagy and apoptosis are essential for the maintenance of homeostasis and normal development in cells and tissues. We found that Bax-interacting factor 1 (Bif-1/Endophillin B1/SH3GLB1), involving in autophagy and apoptosis, was upregulated during osteoclastogenesis. Furthermore, mature osteoclasts expressed Bif-1 in the cytosol, particularly the perinuclear regions and podosome, suggesting that Bif-1 regulates osteoclastic bone resorption. Bif-1-deficient (Bif-1 -/- ) mice showed increased trabecular bone volume and trabecular number. Histological analyses indicated that the osteoclast numbers increased in Bif-1 -/- mice. Consistent with the in vivo results, osteoclastogenesis induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) was accelerated in Bif-1 -/- mice without affecting RANKL-induced activation of RANK downstream signals, such as NF-κB and mitogen-activated protein kinases (MAPKs), CD115/RANK expression in osteoclast precursors, osteoclastic bone-resorbing activity and the survival rate. Unexpectedly, both the bone formation rate and osteoblast surface substantially increased in Bif-1 -/- mice. Treatment with β-glycerophosphate (β-GP) and ascorbic acid (A.A) enhanced osteoblastic differentiation and mineralization in Bif-1 -/- mice. Finally, bone marrow cells from Bif-1 -/- mice showed a significantly higher colony-forming efficacy by the treatment with or without β-GP and A.A than cells from wild-type (WT) mice, suggesting that cells from Bif-1 -/- mice had higher clonogenicity and self-renewal activity than those from WT mice. In summary, Bif-1 might regulate bone homeostasis by controlling the differentiation and function of both osteoclasts and osteoblasts.

DOI： doi: 10.1002/jcb.29193.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Endochondral ossification is important for skeletal development. Recent findings indicate that the p65 (RelA) subunit, a main subunit of the classical nuclear factor-κB (NF-κB) pathway, plays essential roles in chondrocyte differentiation. Although several groups have reported that the alternative NF-κB pathway also regulates bone homeostasis, the role of the alternative NF-κB pathway in chondrocyte development is still unclear. Here, we analyzed the in vivo function of the alternative pathway on endochondral ossification using p100-deficient (p100-/-) mice, which carry a homozygous deletion of the COOH-terminal ankyrin repeats of p100 but still express functional p52 protein. The alternative pathway was activated during the periarticular stage in wild-type mice. p100-/- mice exhibited dwarfism, and histological analysis of the growth plate revealed abnormal arrangement of chondrocyte columns and a narrowed hypertrophic zone. Consistent with these observations, the expression of hypertrophic chondrocyte markers, type X collagen (ColX) or matrix metalloproteinase 13, but not early chondrogenic markers, such as Col II or aggrecan, was suppressed in p100-/- mice. An in vivo BrdU tracing assay clearly demonstrated less proliferative activity in chondrocytes in p100-/- mice. These defects were partly rescued when the RelB gene was deleted in p100-/- mice. Taken together, the alternative NF-κB pathway may regulate chondrocyte proliferation and differentiation to maintain endochondral ossification.

DOI： doi: 10.1002/jcb.29193.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osteoclasts resorb bone by attaching on the bone matrix and forming a sealing zone. In Src-deficient mice, osteoclasts cannot form the actin ring, a characteristic actin structure that seals the resorbed area, and resorb hardly any bone as a result. However, the molecular mechanism underlying the role of Src in the regulation and organization of the actin ring is still unclear. We identified an actin-regulatory protein, protein phosphatase 1 regulatory subunit 18 (PPP1r18), as an Src-binding protein in an Src-, Yes-, and Fyn-deficient fibroblast (SYF) cell line overexpressing a constitutively active form of Src. PPP1r18 was localized in the nucleus and actin ring. PPP1r18 overexpression in osteoclasts inhibited terminal differentiation, actin ring formation, and bone-resorbing activity. A mutation of the protein phosphatase 1 (PP1)-binding domain of PPP1r18 rescued these phenotypes. In contrast, PPP1r18 knockdown promoted terminal differentiation and actin ring formation. In summary, we showed that PPP1r18 likely plays a role in podosome organization and bone resorption.

DOI： 10.1128/MCB.00425-17

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bone morphogenetic protein (BMP) potentiates bone formation through the Smad signaling pathway in vitro and in vivo. The transcription factor nuclear factor κB (NF-κB) suppresses BMP-induced osteoblast differentiation. Recently, we identified that the transactivation (TA) 2 domain of p65, a main subunit of NF-κB, interacts with the mad homology (MH) 1 domain of Smad4 to inhibit BMP signaling. Therefore, we further attempted to identify the interacting regions of these two molecules at the amino acid level. We identified a region that we term the Smad4-binding domain (SBD), an amino-terminal region of TA2 that associates with the MH1 domain of Smad4. Cell-permeable SBD peptide blocked the association of p65 with Smad4 and enhanced BMP2-induced osteoblast differentiation and mineralization without affecting the phosphorylation of Smad1/5 or the activation of NF-κB signaling. SBD peptide enhanced the binding of the BMP2-inudced phosphorylated Smad1/5 on the promoter region of inhibitor of DNA binding 1 (Id-1) compared with control peptide. Although SBD peptide did not affect BMP2-induced chondrogenesis during ectopic bone formation, the peptide enhanced BMP2-induced ectopic bone formation in subcortical bone. Thus, the SBD peptide is useful for enabling BMP2-induced bone regeneration without inhibiting NF-κB activity.

DOI： 10.1002/jcp.26571

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS. Fukushima et al. demonstrated that the sustained osteoclast activity in Hajdu-Cheney syndrome (HCS) is largely due to elevated protein abundance of the C terminus truncating NOTCH2 mutant that escapes FBW7-mediated ubiquitination and proteolysis, suggesting that the FBW7/NOTCH2 signaling pathway is a potential therapeutic target for osteolytic bone disorders, including HCS.

DOI： 10.1016/j.molcel.2017.10.018

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Satellite cells are skeletal muscle stem cells that provide myonuclei for postnatal muscle growth, maintenance, and repair/ regeneration in adults. Normally, satellite cells are mitotically quiescent, but they are activated in response to muscle injury, in which case they proliferate extensively and exhibit up-regulated expression of the transcription factor MyoD, a master regulator of myogenesis. MyoD forms a heterodimer with E proteins through their basic helix-loop-helix domain, binds to E boxes in the genome and thereby activates transcription at muscle-specific promoters. The central role of MyoD in muscle differentiation has increased interest in finding potential MyoD regulators. Here we identified transducin-like enhancer of split (TLE3), one of the Groucho/TLE family members, as a regulator of MyoD function during myogenesis. TLE3 was expressed in activated and proliferative satellite cells in which increased TLE3 levels suppressed myogenic differentiation, and, conversely, reduced TLE3 levels promoted myogenesis with a concomitant increase in proliferation. We found that, via its glutamine- and serine/proline-rich domains, TLE3 interferes with MyoD function by disrupting the association between the basic helix-loop-helix domain of MyoD and E proteins. Our findings indicate that TLE3 participates in skeletal muscle homeostasis by dampening satellite cell differentiation via repression of MyoD transcriptional activity.

DOI： 10.1074/jbc.M116.774570

開催年月日： 2019年11月

記述言語：日本語  

開催地：福岡国際会議場   国名：日本国  

開催年月日： 2019年10月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：西日本総合展示場   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：九州大学百年講堂   国名：日本国  

開催年月日： 2017年8月

記述言語：日本語  

開催地：東京医科歯科大学   国名：日本国  

開催年月日： 2017年5月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：西日本総合展示場、北九州、福岡   国名：日本国  

開催年月日： 2024年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：長崎   国名：日本国  

開催年月日： 2024年11月

記述言語：日本語   会議種別：ポスター発表  

開催地：長崎   国名：日本国  

開催年月日： 2024年11月

記述言語：英語   会議種別：ポスター発表  

開催地：長崎   国名：日本国  

開催年月日： 2024年11月

記述言語：日本語   会議種別：ポスター発表  

開催地：長崎   国名：日本国  

開催年月日： 2024年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：長崎   国名：日本国  

開催年月日： 2024年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：長崎   国名：日本国  

開催年月日： 2024年11月

記述言語：日本語  

開催地：長崎   国名：日本国  

開催年月日： 2024年9月

記述言語：英語   会議種別：ポスター発表  

開催地：Toronoto Canada  

開催年月日： 2024年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：沖縄、那覇   国名：日本国  

開催年月日： 2024年6月 - 2024年7月

記述言語：日本語   会議種別：ポスター発表  

開催地：沖縄   国名：日本国  

開催年月日： 2024年6月 - 2024年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：沖縄   国名：日本国  

開催年月日： 2024年4月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：福岡   国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

開催地：東京   国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

国名：日本国  

開催年月日： 2024年4月

記述言語：英語  

国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

開催地：新潟   国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

開催地：福岡   国名：日本国  

開催年月日： 2024年4月

記述言語：英語  

開催地：福岡   国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

開催地：福岡   国名：日本国  

開催年月日： 2024年4月

記述言語：日本語  

開催地：福岡   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：徳島   国名：日本国  

開催年月日： 2022年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：徳島   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：徳島   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：徳島   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：徳島   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：徳島   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2021年10月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2021年10月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2019年10月

記述言語：日本語  

国名：日本国  

開催年月日： 2019年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京歯科大学   国名：日本国  

開催年月日： 2019年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京歯科大学   国名：日本国  

開催年月日： 2019年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京歯科大学   国名：日本国  

開催年月日： 2018年9月 - 2019年9月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：九州大学百年講堂、福岡   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：九州大学百年講堂、福岡   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：九州大学百年講堂、福岡   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：九州大学百年講堂、福岡   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：九州大学百年講堂、福岡   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2018年5月

記述言語：日本語  

国名：日本国  

開催年月日： 2018年5月

記述言語：英語  

国名：日本国  

開催年月日： 2018年5月

記述言語：日本語  

国名：日本国  

開催年月日： 2018年5月

記述言語：日本語  

国名：日本国  

開催年月日： 2018年5月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月 - 2018年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

国名：日本国  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

The nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of genes that control cell proliferation and apoptosis, as well as genes that respond to inflammation and immune responses. There are two means of NF-κB activation: the classical pathway, which involves the degradation of the inhibitor of κBα (IκBα), and the alternative pathway, which involves the NF-κB-inducing kinase (NIK, also known as MAP3K14). The mouse growth plate consists of the resting zone, proliferative zone, prehypertrophic zone, and hypertrophic zone. The p65 (RelA), which plays a central role in the classical pathway, is expressed throughout the cartilage layer, from the resting zone to the hypertrophic zone. Inhibiting the classical NF-κB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis. Since the production of autoantibodies and inflammatory cytokines, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, and IL-17, are regulated by the classical pathways and are increased in rheumatoid arthritis (RA), NF-κB inhibitors are used to suppress inflammation and joint destruction in RA models. In osteoarthritis (OA) models, the strength of NF-κB-activation is found to regulate the facilitation or suppression of OA. On the other hand, RelB is involved in the alternative pathway, and is expressed in the periarticular zone during the embryonic period of development. The alternative pathway is involved in the generation of chondrocytes in the proliferative zone during physiological conditions, and in the development of RA and OA during pathological conditions. Thus, NF-κB is an important molecule that controls normal development and the pathological destruction of cartilage.

DOI： doi: 10.3390/ijms20246275.

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammation and the immune response. The activation of NF-κB occurs via two pathways: inflammatory cytokines, such as TNF-α and IL-1β, activate the "classical pathway", and cytokines involved in lymph node formation, such as CD40L, activate the "alternative pathway". NF-κB1 (p50) and NF-κB2 (p52) double-knockout mice exhibited severe osteopetrosis due to the total lack of osteoclasts, suggesting that NF-κB activation is required for osteoclast differentiation. These results indicate that NF-κB may be a therapeutic target for inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease. On the other hand, mice that express the dominant negative form of IκB kinase (IKK)-β specifically in osteoblasts exhibited increased bone mass, but there was no change in osteoclast numbers. Therefore, inhibition of NF-κB is thought to promote bone formation. Taken together, the inhibition of NF-κB leads to "killing two birds with one stone": it suppresses bone resorption and promotes bone formation. This review describes the role of NF-κB in physiological bone metabolism, pathologic bone destruction, and bone regeneration.

DOI： doi: 10.3390/cells8121636.

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

Purpose of the Review
Vitamins play important roles in bone health, and vitamin supplementation has been recommended to prevent osteoporosis and to reduce fracture risk in the elderly. However, the benefits of vitamin intake for bone health are still controversial. The aim of the review is to examine the relationship between vitamins and bone health and how vitamins function in osteoblasts and osteoclasts.
Recent Findings
A broad literature search with the PubMed database was performed. The results of human clinical studies are inconsistent due to differences in the study design, race, genetic factors, and the population. Vitamin K, E, or C intake seems to benefit for bone health as well as vitamin D. Recent findings did not support the benefit of the vitamin B complex for bone health. Furthermore, both the excess and deficiency of vitamin A might be involved in compromised bone health.
Summary
The well-balanced and adequate amounts of vitamins should be ensured to prevent adverse effects on bone health.

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

骨リモデリングは、破骨細胞による骨吸収と骨芽細胞による骨形成サイクルから成り、骨量とカルシウムの恒常性の維持に重要である。骨吸収と骨形成は密接な関係を保つが、これら２つのバランスが崩れると骨量の増加や減少が生じる。破骨細胞は生理的、または病的骨吸収に関わる多核巨細胞であり、破骨細胞による骨吸収はさまざまなサイトカイン、カルシウムシグナルや転写因子によって制御されている。近年では遺伝子欠損マウスの結果から破骨細胞による骨吸収を制御する新たな分子の重要性が証明されている。本稿では、骨リモデリングを制御する破骨細胞の骨吸収に関する分子機構について最近の知見を概説する。

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

種別：大会・シンポジウム等 

種別：査読等 

外国語雑誌　査読論文数：8

種別：大会・シンポジウム等 

種別：学会・研究会等 

種別：査読等 

外国語雑誌　査読論文数：28

種別：大会・シンポジウム等 

参加者数：300

種別：査読等 

外国語雑誌　査読論文数：43

種別：審査・学術的助言 

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種別：査読等 

外国語雑誌　査読論文数：37

種別：学会・研究会等 

種別：審査・学術的助言 

種別：審査・学術的助言 

種別：査読等 

外国語雑誌　査読論文数：33

国内会議録　査読論文数：1

種別：審査・学術的助言 

種別：大会・シンポジウム等 

参加者数：1,000

種別：学会・研究会等 

種別：査読等 

外国語雑誌　査読論文数：20

種別：審査・学術的助言 

種別：査読等 

外国語雑誌　査読論文数：19

種別：学会・研究会等