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Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis

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Bone Research 2019年第1期7卷 66-75页

作者： Yuta Nakai Kazuo Okamoto Asuka Terashima Shogo Ehata Jun Nishida takeshi imamura Takashi Ono Hiroshi Takayanagi Department of Immunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyoJapan Department of Orthodontic Science Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityYushima 1-5-45Bunkyo-kuTokyoJapan Department of Osteoimmunology Graduate School of Medicine and Faculty of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyoJapan Department of Molecular Pathology Graduate School of MedicineThe University of TokyoHongo 7-3-1Bunkyo-kuTokyoJapan Department of Molecular Medicine for Pathogenesis Ehime University Graduate School of MedicineShitsukawaToonEhimeJapan

Bone is one of the preferred sites for the metastasis of malignant tumours,such as breast cancer,lung cancer and malignant *** cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand(RANKL),which promotes osteoclast differentiation and ***-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth,causing bone pain and ***,RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor,*** inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis,and a human monoclonal anti-RANKL antibody,denosumab,has been used in the ***,orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to *** we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse *** administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced ***2676293 suppressed RANKLmediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10,which is known not to trigger osteoclast *** on the results from this study,RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.

关键词： Bone tumours metastasis

A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

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Bone Research 2020年第4期8卷 429-438页

作者： Junichi Kushioka Takashi Kaito Rintaro Okada Hiroyuki Ishiguro Zeynep Bal Joe Kodama Ryota Chijimatsu Melanie Pye Masahiro Narimatsu Jeffrey LWrana Yasumichi Inoue Hiroko Ninomiya Shin Yamamoto Takashi Saitou Hideki Yoshikawa takeshi imamura Department of Orthopaedic Surgery Osaka University Graduate School of Medicine2-2 YamadaokaSuitaOsaka 565-0871Japan Bone and Cartilage Regenerative Medicine The University of Tokyo7-3-1HongoBunkyo-kuTokyo 113-8655Japan Centre for Systems Biology Lunenfeld-Tanenbaum Research InstituteMount Sinai Hospital600 University AveTorontoON M5G 1X5Canada Department of Cell Signaling Graduate School of Pharmaceutical SciencesNagoya City University3-1 Tanabe-doriMizuho-kuNagoyaAichi 467-8603Japan Department of Molecular Medicine for Pathogenesis Ehime University Graduate School of Medicine454 ShitsukawaToonEhime 791-0295Japan Department of Gastroenterology and Metabology Ehime University Graduate School of Medicine454 ShitsukawaToonEhime 791-0295Japan Translational Research Center Ehime University Hospital454 ShitsukawaToonEhime 791-0295Japan

Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone *** ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP *** Smurf2 has been shown to negatively regulate TGF-β/Smad signaling,its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly *** the present study,we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone *** collagen sponges containing 3μg of recombinant human BMP2(rhBMP2)were implanted in the dorsal muscle pouches of wild type(WT)and Smurf2−/−*** rhBMP2-induced ectopic bone in Smurf2−/−mice showed greater bone mass,higher mineral apposition and bone formation rates,and greater osteoblast numbers than the ectopic bone in WT *** WT mice,the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular *** contrast,in Smurf2−/−mice,the induced bone consisted of a thick,continuous outer cortical shell and abundant inner trabecular ***,rhBMP2-stimulated bone marrow stromal cells(BMSCs)from Smurf2−/−mice showed increased osteogenic ***2 induced the ubiquitination of Smad1/***/Smad signaling was enhanced in Smurf2−/−BMSCs stimulated with rhBMP2,and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these *** findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling,thereby identifying a new regulatory mechanism in bone metabolism.

关键词： Smurf2 metabolism involvement

Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

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Bone Research 2023年第2期11卷 340-353页

作者： takeshi Oichi Joe Kodama Kimberly Wilson Hongying Tian Yuka imamura Kawasawa Yu Usami Yasushi Oshima Taku Saito Sakae Tanaka Masahiro Iwamoto Satoru Otsuru Motomi Enomoto-Iwamoto Department of Orthopedics School of MedicineUniversity of MarylandBaltimoreMD21201USA Sensory&Motor System Medicine Faculty of MedicineThe University of TokyoBunkyo-kuTokyo1138655Japan Department of Orthopedics Teikyo University School of MedicineTokyo1738608Japan Department of Biochemistry and Molecular Biology Pennsylvania State University College of MedicineHersheyPA17033USA Department of Oral Pathology Osaka University Graduate School of DentistrySuitaOsaka5650871Japan

Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by *** chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth *** is a leading cause of growth retardation in children;however,after recovery from nutrient deprivation,bone growth is accelerated beyond the normal rate,a phenomenon termed catch-up *** nutritional status is a known regulator of long bone growth,it is largely unknown whether and how chondroprogenitor cells respond to deviations in nutrient ***,using fate-mapping analysis in Axin2CreERT2 mice,we showed that dietary restriction increased the number of Axin2+chondroprogenitors in the resting zone and simultaneously inhibited their *** nutrient deficiency was resolved,the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns,contributing to accelerated ***,we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone and that exogenous IGF-1 restored the phosphorylated Akt level and stimulated differentiation of the pooled chondroprogenitors,decreasing their *** study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of chondroprogenitor cells.

关键词： progenitor plate maintain

Improvement in symptoms after H_2-receptor antagonist-based therapy for eradication of H pylori infection

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World Journal of Gastroenterology 2007年第28期13卷 3836-3840页

作者： takeshi Hagiwara Mototsugu Kato Tomonori Anbo Akimichi imamura Toshihiro Suga Takumi Uchida Akira Fujinaga Manabu Nakagawa Soichi Nakagawa Yuichi Shimizu Jyunji Yamamoto Hiroshi Takeda Masahiro Asaka Department of Gastroenterology Sapporo-Kosei General HospitalSapporoHokkaido 060-4876Japan Division of Endoscopy Hokkaido University HospitalSapporoHokkaido 060-4876Japan Department of Internal Medicine Abashiri-Kosei General HospitalAbashiriJapan Department of Gastroenterology Graduate School of Medicine Hokkaido UniversitySapporoHokkaido 060-4876Japan

AIM: To investigate the therapeutic effects of triple therapy combining lafutidine with clarithromycin and amoxicillin on H pylori infection and the resolution of gastroesophageal symptoms after eradication. METHODS: We conducted a randomized, multicenter, open-label controlled trial to compare the effective-ness of a triple therapy of lafutidine, clarithromycin, and amoxicillin (lafutidine group) with that of a triple therapy of lansoprazole, clarithromycin, and amoxicillin (lansopra- zole group) in patients with H pylori infection. The study group comprised 22 patients with gastric ulcers and 18 patients with duodenal ulcers who had H pylori infection. RESULTS: H pylori eradication rates were similar in the lafutidine group (14/20, 70%) and the lansoprazole group (14/20, 70%). Gastroesophageal reflux and ab-dominal symptoms improved after eradication therapy in both groups, whereas abdominal discomfort, diarrhea, and constipation were unchanged. H pylori status had no apparent effect on improvement of gastroesophageal reflux or abdominal symptoms after treatment. Adverse events were similar in both groups. CONCLUSION: The triple therapy including lafutidine is equivalent to triple therapy including lansoprazole in terms of H pylori eradication rates and improvement in gastroesophageal reflux and abdominal *** results are attributed to the fact that lafutidine has strong, continuous antisecretory activity, unaffected by CYP2C19 polymorphisms.

关键词： Hpylori Gastroesophageal symptoms Lafutidine Lansoprazole

骨髓造血细胞来源的半乳糖苷凝集素导致细胞和系统胰岛素抵抗

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科学新闻 2017年第4期 40-40页

作者：李平平 Shuainan Liu Min Lu Gautum Bandyopadhyay Dayoung Oh takeshi imamura Andrew M.F.Johnson Dorothy Sears Zhufang Shen Bing Cui Lijuan Kong Shaocong Hou Xiao Liang Salvatore Iovino Steven M.Watkins Wei Ying Olivia Osborn Joshua Wollam Martin Brenner Jerrold M.Olefsky 中国医学科学院药物研究所

文章简介肥胖时巨噬细胞与其他免疫细胞在胰岛素靶组织大量聚集,构成一种慢性炎症状态和胰岛素抵抗。半乳糖苷凝集素Galectin-3(Gal3)主要来源于巨噬细胞。无论在肥胖小鼠或者肥胖病人,Gal3水平明显增加。Gal3给药可让正常小鼠诱发胰岛... 详细信息

文章简介肥胖时巨噬细胞与其他免疫细胞在胰岛素靶组织大量聚集,构成一种慢性炎症状态和胰岛素抵抗。半乳糖苷凝集素Galectin-3(Gal3)主要来源于巨噬细胞。无论在肥胖小鼠或者肥胖病人,Gal3水平明显增加。Gal3给药可让正常小鼠诱发胰岛素抵抗和糖耐量异

关键词：胰岛素抵抗炎症病理凝集素细胞

Gastric carcinoma originating from the heterotopic submucosal gastric gland treated by laparoscopy and endoscopy cooperative surgery

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World Journal of Gastrointestinal Oncology 2015年第8期7卷 118-122页

作者： Taisuke imamura Shuhei Komatsu Daisuke Ichikawa Hiroki Kobayashi Mahito Miyamae Shoji Hirajima Tsutomu Kawaguchi takeshi Kubota Toshiyuki Kosuga Kazuma Okamoto Hirotaka Konishi Atsushi Shiozaki Hitoshi Fujiwara Kiyoshi Ogiso Nobuaki Yagi Akio Yanagisawa Takashi Ando Eigo Otsuji Division of Digestive Surgery Department of Digestive Surgery Kyoto Prefectural University of Medicine Kyoto 602-8566 Japan Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Kyoto 602-8566 Japan Department of Pathology Kyoto Prefectural University of Medicine Kyoto 602-8566 Japan Department of Gastroenterology and Hepatology Kyoto Kuramaguchi Medical Center Kyoto 603-8151 Japan

Gastric carcinoma is derived from epithelial cells in the gastric mucosa. We reported an extremely rare case of submucosal gastric carcinoma originating from the heterotopic submucosal gastric gland(HSG) that was safely diagnosed by laparoscopy and endoscopy cooperative surgery(LECS). A 66-year-old man underwent gastrointestinal endoscopy, which detected a submucosal tumor(SMT) of 1.5 cm in diameter on the lesser-anterior wall of the upper gastric body. The tumor could not be diagnosed histologically, even by endoscopic ultrasound-guided fine-needle aspiration biopsy. Local resection by LECS was performed to confirm a diagnosis. Pathologically, the tumor was an intra-submucosal well differentiated adenocarcinoma invading 5000 μm intothe submucosal layer. The resected tumor had negative lateral and vertical margins. Based on the Japanese treatment guidelines, additional laparoscopic proximal gastrectomy was curatively performed. LECS is a less invasive and safer approach for the diagnosis of SMT, even in submucosal gastric carcinoma originating from the HSG.

关键词： Heterotopic submucosal gland Laparoscopyand endoscopy cooperative surgery Gastric carcinoma Gastric submucosal tumor Less invasive treatment