| 1. |
Aoki T, Hiura F, Li A, Yang N, Takakura-Hino N, Mukai S, Matsuda M, Nishimura F, Jimi E., Inhibition of non-canonical NF-B signaling suppresses periodontal inflammation and bone loss., Front Immunol., 10.3389/fimmu.2023.1179007., 2023.04.  |
| 2. |
Gao J, Li A, Fujii S, Huang F, Nakatomi C, Nakmura I, Honda H, Kiyoshima T, Jimi E., p130Cas is required for androgen-dependent postnatal development regulation of submandibular glands., Sci Rep., 10.1038/s41598-023-32390-1., 2023.03. |
| 3. |
Hayashi Y, Kimura S, Yano E, Yoshimoto S, Saeki A, Yasukochi A, Hatakeyama Y, Moriyama M, Nakamura S, Jimi E, Kawakubo-Yasukochi T., Id4 modulates salivary gland homeostasis and its expression is downregulated in IgG4-related disease via miR-486-5p., Biochim Biophys Acta Mol Cell Res., 10.1016/j.bbamcr.2022.119404., 2023.02. |
| 4. |
Hiura F, Kawabata Y, Aoki T, Mizokami A, Jimi E., Inhibition of the ATG4-LC3 pathway suppressed osteoclast maturation., Biochem Biophys Res Commun., doi: 10.1016/j.bbrc.2022.09.065., 2023.12. |
| 5. |
Mori M, Mizokami A, Sano T, Mukai S, Hiura F, Ayukawa A, Koyano K, Kanematsu T, Jimi E., RANKL elevation activates the NIK/NF-κB pathway, inducing obesity in ovariectomized mice., J Endocrinol., 10.1530/JOE-21-0424, 2022.04. |
| 6. |
Gao J, Mizokami A, Takeuchi H, Li A, Huang F, Nagano H, Kanematsu T, Jimi E, Hirata M., Phospholipase C-related catalytically inactive protein acts as a positive regulator for insulin signalling in adipocytes., J Cell Sci. 2022 135(1):jcs258584., 10.1242/jcs.258584., 2022.04. |
| 7. |
Kawakubo-Yasukochi T, Yano E, Kimura S, Nishinakagawa T, Mizokami A, Hayashi Y, Hatakeyama Y, Ohe K, Yasukochi A, Nakamura S, Jimi E, Hirata M. , Hepatic glycogenolysis is determined by maternal high-calorie diet via methylation of Pygl and this is modified by osteocalcin administration in mice., Mol Metab. , 10.1016/j.molmet.2021.101360., 2021.10. |
| 8. |
Fujii S, Ishibashi T, Kokura M, Fujimoto T, Matsumoto S, Shidara S, Kurppa KJ, Pape J, Caton J, Morgan PR, Heikinheimo K, Kikuchi A, Jimi E, Kiyoshima T., RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation., J Pathol., 10.1002/path.5814., 2021.10. |
| 9. |
Inoue A, Kiyoshima T, Yoshizaki K, Nakatomi C, Nakatomi M, Ohshima H, Shin M, Gao J, Tsuru K, Okabe K, Nakamura I, Honda H, Matsuda M, Takahashi I, Jimi E., Deletion of epithelial cell-specific p130Cas impairs the maturation stage of amelogenesis., Bone, 10.1016/j.bone.2021.116210, 154, 116210, 2021.11. |
| 10. |
Gao J, Muroya R, Huang F, Nagata K, Shin M, Nagano R, Tajiri Y, Fujii S, Yamaza T, Aoki K, Tamura Y, Inoue M, Chishaki S, Kukita T, Okabe K, Matsuda M, Mori Y, Kiyoshima T, Jimi E., Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1/5 signaling pathway. , Lab Invest. , 10.1038/s41374-021-00661-y., 101, 1475-1483, 2021.11. |
| 11. |
Mukai S, Mizokami A, Otani T, Sano T, Matsuda M, Chishaki S, Gao, Kawakubo-Yasukochi T, Tang R, Kanematsu T, Takeuchi H, Jimi E, Hirata M., Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis., J Biol Chem., doi: 10.1016/j.jbc.2021.100274. , 296, 2021.01. |
| 12. |
Yoshimoto S, Matsuda M, Kato K, Jimi E, Takeuchi H, Nakano S, Kajioka S, Matsuzaki E, Hirofuji T, Inoue R, Hirata M, Morita H., Volume-regulated chloride channel regulates cell proliferation and is involved in the possible interaction between TMEM16A and LRRC8A in human metastatic oral squamous cell carcinoma cells., Eur J Pharmacol., 10.1016/j.ejphar.2021.173881., 895, 173881, 2021.03. |
| 13. |
Hirata-Tsuchiya S, Suzuki S, Okamoto K, Saito N, Yuan H, Yamada S, Jimi E, Shiba H, Kitamura C., A small nuclear acidic protein (MTI-II, Zn2+-binding protein, parathymosin) attenuates TNF-α inhibition of BMP-induced osteogenesis by enhancing accessibility of the Smad4-NF-κB p65 complex to Smad binding element. , Mol Cell Biochem, doi: 10.1007/s11010-020-03734-6, 2020.04, 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.. |
| 14. |
Takakura N, Matsuda M, Khan M, Hiura F, Aoki K, Hirohashi Y, Mori K, Yasuda H, Hirata M, Kitamura C, Jimi E., A novel inhibitor of NF-κB-inducing kinase prevents bone loss by inhibiting osteoclastic bone resorption in ovariectomized mice., Bone, doi: 10.1016/j.bone.2020.115316., 2020.03, 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.. |
| 15. |
Yaginuma T, Gao J, Nagata K, Muroya R, Fei H, Nagano H, Chishaki S, Matsubara T, Kokabu S, Matsuo K, Kiyoshima T, Yoshioka I, Jimi E., p130Cas induces bone invasion by oral squamous cell carcinoma by regulating tumor epithelial-mesenchymal transition and cell proliferation., Carcinogenesis, 10.1093/carcin/bgaa007., 2020.01, 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. |
| 16. |
Kobayakawa M, Matsubara T, Mizokami A, Hiura F, Takakura N, Kokabu S, Matsuda M, Yasuda H, Nakamura I, Takei Y, Honda H, Hosokawa R, Jimi E., Kif1c regulates osteoclastic bone resorption as a downstream molecule of p130Cas., Cell Biochem Funct., doi: 10.1002/cbf.3476., 2019.12, 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.. |
| 17. |
Mizokami A, Mukai S, Gao J, Kawakubo-Yasukochi T, Otani T, Takeuchi H, Jimi E, Hirata M., GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin., J Endocrinol., 2019.11. |
| 18. |
Touyama K, Khan M, Aoki K, Matsuda M, Hiura F, Takakura N, Matsubara T, Harada Y, Hirohashi Y, Tamura Y, Gao J, Mori K, Kokabu S, Yasuda H, Fujita Y, Watanabe K, Takahashi Y, Maki K, Jimi E., Bif-1/Endophilin B1/SH3GLB1 regulates bone homeostasis., J Cell Biochem, doi: 10.1002/jcb.29193., 120, 11, 18793-18804, 2019.11, 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.. |
| 19. |
Nakatomi C, Nakatomi M, Matsubara T, Komori T, Doi-Inoue T, Ishimaru N, Weih F, Iwamoto T, Matsuda M, Kokabu S, Jimi E., Constitutive activation of the alternative NF-κB pathway disturbs endochondral ossification., Bone, doi: 10.1002/jcb.29193., 121, 29-41, 2019.04, 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.. |
| 20. |
Takuma Matsubara, Shoichiro Kokabu, Chihiro Nakatomi, Masayuki Kinbara, Toshihiro Maeda, Mitsuhiro Yoshizawa, Hisataka Yasuda, Teruko Takano-Yamamoto, Roland Baron, Eijiro Jimi, The actin-binding protein PPP1r18 regulates maturation, actin organization, and bone resorption activity of osteoclasts, Molecular and Cellular Biology, 10.1128/MCB.00425-17, 38, 4, 2018.02, 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.. |
| 21. |
Otani T, Matsuda M, Mizokami A, Kitagawa N, Takeuchi H, Jimi E, Inai T, Hirata M., Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes via activation of p300., Cell Death Dis. 2018 13: 1194, 13, 1194, 2018.12. |
| 22. |
Mariko Urata, Shoichiro Kokabu, Takuma Matsubara, Goro Sugiyama, Chihiro Nakatomi, Hiroshi Takeuchi, Shizu Hirata-Tsuchiya, Kazuhiro Aoki, Yukihiko Tamura, Yasuko Moriyama, Yasunori Ayukawa, Miho Matsuda, Min Zhang, Kiyoshi Koyano, Chiaki Kitamura, Eijiro Jimi, A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis, Journal of Cellular Physiology, 10.1002/jcp.26571, 2018.01, 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.. |
| 23. |
Hidefumi Fukushima, Kouhei Shimizu, Asami Watahiki, Seira Hoshikawa, Tomoki Kosho, Daiju Oba, Seiji Sakano, Makiko Arakaki, Aya Yamada, Katsuyuki Nagashima, Koji Okabe, Satoshi Fukumoto, Eijiro Jimi, Anna Bigas, Keiichi Nakayama, Keiko Nakayama, Yoko Aoki, Wenyi Wei, Hiroyuki Inuzuka, NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis, Molecular Cell, 10.1016/j.molcel.2017.10.018, 68, 4, 645-658, 2017.11, 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.. |
| 24. |
Shoichiro Kokabu, Chihiro Nakatomi, Takuma Matsubara, Yusuke Ono, William N. Addison, Jonathan W. Lowery, Mariko Urata, Aaron M. Hudnall, Suzuro Hitomi, Mitsushiro Nakatomi, Tsuyoshi Sato, Kenji Osawa, Tetsuya Yoda, Vicki Rosen, Eijiro Jimi, The transcriptional co-repressor TLE3 regulates myogenic differentiation by repressing the activity of the MyoD transcription factor, Journal of Biological Chemistry, 10.1074/jbc.M116.774570, 292, 31, 12885-12894, 2017.01, 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.. |
