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Article ; Online: Role of RANKL in cancer development and metastasis.

Okamoto, Kazuo

2021 Volume 39, Issue 1, Page(s) 71–81

Abstract: Bone metastasis involves tumor-induced osteoclast activation, resulting in skeletal tumor progression as well as skeletal disorders. Aberrant expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for osteoclast differentiation, ... ...

Abstract	Bone metastasis involves tumor-induced osteoclast activation, resulting in skeletal tumor progression as well as skeletal disorders. Aberrant expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for osteoclast differentiation, induced by the metastatic tumor cells is responsible for the pathological bone resorption in bone metastasis. A fully human anti-RANKL neutralizing antibody has been developed to block osteoclast activation and is now used for the treatment of patients with bone metastasis and multiple myeloma. On the other hand, numerous studies have revealed that the RANKL/RANK system also contributes to primary tumorigenesis as well as metastasis through osteoclast-independent processes. Furthermore, emerging clinical and preclinical evidence has suggested anti-tumor immune effects of RANKL blockade when added to immune checkpoint inhibitor therapies. Study on the pleiotropic functions of RANKL in tumorigenesis and metastasis is now expanding beyond the bone field and has been established as one of the most important areas of "RANKL biology".
MeSH term(s)	Animals ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Clinical Trials as Topic ; Humans ; Neoplasm Metastasis ; Osteoblasts/metabolism ; Osteoblasts/pathology ; RANK Ligand/metabolism
Chemical Substances	RANK Ligand
Language	English
Publishing date	2021-01-02
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	1295123-7
ISSN	1435-5604 ; 0914-8779
ISSN (online)	1435-5604
ISSN	0914-8779
DOI	10.1007/s00774-020-01182-2
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Article ; Online: Effect of T cells on bone.

Okamoto, Kazuo / Takayanagi, Hiroshi

Bone

2023 Volume 168, Page(s) 116675

Abstract: Bone and immune systems mutually influence each other by sharing a variety of regulatory molecules and the tissue microenvironment. The interdisciplinary research field "osteoimmunology" has illuminated the complex and dynamic interactions between the ... ...

Abstract	Bone and immune systems mutually influence each other by sharing a variety of regulatory molecules and the tissue microenvironment. The interdisciplinary research field "osteoimmunology" has illuminated the complex and dynamic interactions between the two systems in the maintenance of tissue homeostasis as well as in the development of immune and skeletal disorders. T cells play a central role in the immune response by secreting various immune factors and stimulating other immune cells and structural cells such as fibroblasts and epithelial cells, thereby contributing to pathogen elimination and pathogenesis of immune diseases. The finding on regulation of osteoclastic bone resorption by activated CD4
MeSH term(s)	Humans ; Arthritis, Rheumatoid ; Bone and Bones/metabolism ; Bone Resorption/metabolism ; Osteoclasts/metabolism ; T-Lymphocytes/metabolism
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2023.116675
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Zs.A 1571: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: [Regulation of bone by IL-17-producing T cells].

Okamoto, Kazuo

Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology

2017 Volume 40, Issue 5, Page(s) 361–366

Abstract: Bone is a component of the skeletal-locomotor system but also functions as an immunological organ that harbors hematopoietic stem and progenitor cells. Since the immune and skeletal systems are closely related through a number of shared regulatory ... ...

Abstract	Bone is a component of the skeletal-locomotor system but also functions as an immunological organ that harbors hematopoietic stem and progenitor cells. Since the immune and skeletal systems are closely related through a number of shared regulatory molecules including cytokines and receptors, bone can be affected in various immune disorders. Rheumatoid arthritis is a typical disease in which the immune system affects the bone metabolism. The enhanced activity of osteoclasts by the activation of Th17 cells causes the joint destruction in rheumatoid arthritis. Studies on bone destruction associated rheumatoid arthritis have highlighted the importance of the interplay between the immune and bone systems, and promoted the new interdisciplinary field of "osteoimmunology". Furthermore, recent studies have suggested that regulation of bone tissues by IL-17 is more complicated than we had expected. IL-17-prodcuing cells contribute to new bone formation at the enthesis in ankylosing spondylitis, and IL-17-producing γδ T cells promote bone regeneration by acting on the mesenchymal stem cells in bone fracture healing. It would be necessary to comprehensively understand the interplay between the immune and bone systems for elucidation of the molecular mechanisms underlying the pathogenesis of various diseases that involves the two systems.
MeSH term(s)	Animals ; Arthritis, Rheumatoid/immunology ; Arthritis, Rheumatoid/pathology ; Bone Regeneration/genetics ; Bone and Bones/cytology ; Bone and Bones/immunology ; Bone and Bones/metabolism ; Bone and Bones/pathology ; Hematopoietic Stem Cells ; Humans ; Interleukin-17/metabolism ; Interleukin-17/physiology ; Intraepithelial Lymphocytes/immunology ; Intraepithelial Lymphocytes/physiology ; Mesenchymal Stromal Cells/immunology ; Mesenchymal Stromal Cells/physiology ; Mice ; Osteoblasts/immunology ; Osteoblasts/physiology ; Osteoclasts/immunology ; Osteoclasts/physiology ; Osteogenesis/genetics ; Stem Cells ; Th17 Cells/immunology
Chemical Substances	Interleukin-17
Language	Japanese
Publishing date	2017
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	2019767-6
ISSN	1349-7413 ; 0911-4300
ISSN (online)	1349-7413
ISSN	0911-4300
DOI	10.2177/jsci.40.361
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Article ; Online: Osteoimmunology.

Okamoto, Kazuo / Takayanagi, Hiroshi

Cold Spring Harbor perspectives in medicine

2019 Volume 9, Issue 1

Abstract: Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory ... ...

Abstract	Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory molecules, including cytokines and signaling molecules. Osteoimmunology was created as an interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, the importance of an inseparable link between the two systems has been highlighted by studies on the pathogenesis of rheumatoid arthritis (RA), in which pathogenic helper T cells induce the progressive destruction of multiple joints through aberrant expression of receptor activator of nuclear factor (NF)-κB ligand (RANKL). The conceptual bridge of osteoimmunology provides not only a novel framework for understanding these biological systems but also a molecular basis for the development of therapeutic approaches for diseases of bone and/or the immune system.
MeSH term(s)	Animals ; Arthritis, Rheumatoid/immunology ; Arthritis, Rheumatoid/metabolism ; Bone Diseases/immunology ; Bone Diseases/metabolism ; Bone Remodeling/immunology ; Bone and Bones/immunology ; Humans ; Immune System/metabolism ; Mice ; RANK Ligand/immunology ; Receptor Cross-Talk ; Signal Transduction ; T-Lymphocytes/immunology
Chemical Substances	RANK Ligand
Language	English
Publishing date	2019-01-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a031245
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Article: Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling.

Ono, Takehito / Denda, Ryosuke / Tsukahara, Yuta / Nakamura, Takashi / Okamoto, Kazuo / Takayanagi, Hiroshi / Nakashima, Tomoki

Bone research

2022 Volume 10, Issue 1, Page(s) 52

Abstract: Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden. Physical exercise at times can be an effective remedy for frailty, but exercise therapy cannot be applied in all ... ...

Abstract	Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden. Physical exercise at times can be an effective remedy for frailty, but exercise therapy cannot be applied in all clinical cases. Medication is safer than exercise, but there are no drugs that reinforce both muscle and bone when administered alone. Multiple medications increase the risk of adverse events; thus, there is a need for individual drugs targeting both tissues. To this end, we established a novel sequential drug screening system and identified an aminoindazole derivative, locamidazole (LAMZ), which promotes both myogenesis and osteoblastogenesis while suppressing osteoclastogenesis. Administration of this drug enhanced locomotor function, with muscle and bone significantly strengthened. Mechanistically, LAMZ induced Mef2c and PGC-1α in a calcium signaling-dependent manner. As this signaling is activated upon physical exercise, LAMZ mimics physical exercise. Thus, LAMZ is a promising therapeutic drug for locomotor diseases, including sarcopenia and osteoporosis.
Language	English
Publishing date	2022-08-03
Publishing country	China
Document type	Journal Article
ZDB-ID	2803313-9
ISSN	2095-6231 ; 2095-4700
ISSN (online)	2095-6231
ISSN	2095-4700
DOI	10.1038/s41413-022-00225-w
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Article: Identification of an intronic enhancer regulating RANKL expression in osteocytic cells.

Yan, Minglu / Tsukasaki, Masayuki / Muro, Ryunosuke / Ando, Yutaro / Nakamura, Kazutaka / Komatsu, Noriko / Nitta, Takeshi / Okamura, Tadashi / Okamoto, Kazuo / Takayanagi, Hiroshi

Bone research

2023 Volume 11, Issue 1, Page(s) 43

Abstract: The bony skeleton is continuously renewed throughout adult life by the bone remodeling process, in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms. Osteocytes regulate bone remodeling by producing the osteoclast ... ...

Abstract	The bony skeleton is continuously renewed throughout adult life by the bone remodeling process, in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms. Osteocytes regulate bone remodeling by producing the osteoclast differentiation factor RANKL (encoded by the TNFSF11 gene). However, the precise mechanisms underlying RANKL expression in osteocytes are still elusive. Here, we explored the epigenomic landscape of osteocytic cells and identified a hitherto-undescribed osteocytic cell-specific intronic enhancer in the TNFSF11 gene locus. Bioinformatics analyses showed that transcription factors involved in cell death and senescence act on this intronic enhancer region. Single-cell transcriptomic data analysis demonstrated that cell death signaling increased RANKL expression in osteocytic cells. Genetic deletion of the intronic enhancer led to a high-bone-mass phenotype with decreased levels of RANKL in osteocytic cells and osteoclastogenesis in the adult stage, while RANKL expression was not affected in osteoblasts or lymphocytes. These data suggest that osteocytes may utilize a specialized regulatory element to facilitate osteoclast formation at the bone surface to be resorbed by linking signals from cellular senescence/death and RANKL expression.
Language	English
Publishing date	2023-08-11
Publishing country	China
Document type	Journal Article
ZDB-ID	2803313-9
ISSN	2095-6231 ; 2095-4700
ISSN (online)	2095-6231
ISSN	2095-4700
DOI	10.1038/s41413-023-00277-6
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Article: Effect of JAK inhibitors on the three forms of bone damage in autoimmune arthritis: joint erosion, periarticular osteopenia, and systemic bone loss.

Komagamine, Masatsugu / Komatsu, Noriko / Ling, Rui / Okamoto, Kazuo / Tianshu, Shi / Matsuda, Kotaro / Takeuchi, Tsutomu / Kaneko, Yuko / Takayanagi, Hiroshi

Inflammation and regeneration

2023 Volume 43, Issue 1, Page(s) 44

Abstract: Background: The types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three ... ...

Abstract	Background: The types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation. Methods: Collagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (μCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro. Results: The JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling. Conclusions: The JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.
Language	English
Publishing date	2023-09-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2051471-2
ISSN	1880-9693 ; 0389-4290
ISSN	1880-9693 ; 0389-4290
DOI	10.1186/s41232-023-00293-3
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Article ; Online: The neutrophil-osteogenic cell axis promotes bone destruction in periodontitis.

Ando, Yutaro / Tsukasaki, Masayuki / Huynh, Nam Cong-Nhat / Zang, Shizao / Yan, Minglu / Muro, Ryunosuke / Nakamura, Kazutaka / Komagamine, Masatsugu / Komatsu, Noriko / Okamoto, Kazuo / Nakano, Kenta / Okamura, Tadashi / Yamaguchi, Akira / Ishihara, Kazuyuki / Takayanagi, Hiroshi

International journal of oral science

2024 Volume 16, Issue 1, Page(s) 18

Abstract: The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of ... ...

Abstract	The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune-bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNA-sequencing analysis on mouse periodontal lesions and showed that neutrophil-osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.
MeSH term(s)	Humans ; Mice ; Animals ; Neutrophils/metabolism ; Neutrophils/pathology ; Periodontitis ; Cytokines ; Alveolar Bone Loss/microbiology ; Osteogenesis ; RANK Ligand
Chemical Substances	Cytokines ; RANK Ligand
Language	English
Publishing date	2024-02-27
Publishing country	India
Document type	Journal Article
ZDB-ID	2569849-7
ISSN	2049-3169 ; 1674-2818
ISSN (online)	2049-3169
ISSN	1674-2818
DOI	10.1038/s41368-023-00275-8
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Article: In Situ Reactive Compatibilization of Polyamide 6 and Polycarbonate Blend by the Catalytic Effect of Phenol Novolac

Hirai, Takayuki / Yagi, Kenichi / Okamoto, Kazuo / Onochi, Yusaku / Kawada, Jumpei

Industrial & engineering chemistry process design and development. 2020 Jan. 14, v. 59, no. 5

2020

Abstract: Ternary polymer blends of polyamide 6 (PA6), polycarbonate (PC), and phenol novolac (PN) were prepared by a melt mixing process. PN catalyzes the exchange reaction between PA6 and PC and promotes the generation of a copolymer, which improves the ... ...

Abstract	Ternary polymer blends of polyamide 6 (PA6), polycarbonate (PC), and phenol novolac (PN) were prepared by a melt mixing process. PN catalyzes the exchange reaction between PA6 and PC and promotes the generation of a copolymer, which improves the compatibility. Herein, the catalytic effect of PN was experimentally supported by an increase in torque during melt mixing and mass signals from copolymer fragments detected by mass spectroscopy. The characteristic behavior of the exchange reaction changed significantly with increasing PN amount. The promotion of in situ copolymer generation led to the formation of ternary blends, which show homogeneous morphologies and superior mechanical properties, such as high stiffness and good elongation, compared with those of the binary blends without PN. Using excess PN causes some drawbacks like brittleness due to the decomposition of the PC component. A loading amount of 1–3 wt % PN was suitable for achieving a ternary blend with improved properties.
Keywords	brittleness ; catalytic activity ; composite polymers ; mass spectrometry ; melting ; mixing ; phenol ; polyamides ; torque
Language	English
Dates of publication	2020-0114
Size	p. 1855-1861.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1484436-9
ISSN	1520-5045 ; 0888-5885
ISSN (online)	1520-5045
ISSN	0888-5885
DOI	10.1021/acs.iecr.9b05970
Database	NAL-Catalogue (AGRICOLA)

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Article: Microfluidic Fabrication of Morphology-Controlled Polymeric Microspheres of Blends of Poly(4-butyltriphenylamine) and Poly(methyl methacrylate).

Yoshida, Saki / Kikuchi, Shu / Kanehashi, Shinji / Okamoto, Kazuo / Ogino, Kenji

Materials (Basel, Switzerland)

2018 Volume 11, Issue 4

Abstract: Multicomponent polymer particles with specific morphology are promising materials exhibiting novel functionality which cannot be obtained with single-component polymer particles. Particularly, the preparation of such kinds of polymer particles involving ... ...

Abstract	Multicomponent polymer particles with specific morphology are promising materials exhibiting novel functionality which cannot be obtained with single-component polymer particles. Particularly, the preparation of such kinds of polymer particles involving electrically or optically active conjugated polymers with uniform size is a challenging subject due to their intense demands. Here, microspheres of binary polymer blend consisting of poly(4-butyltriphenylamine) (PBTPA)/poly(methyl methacrylate) (PMMA) (1:1 in weight) were produced via a microfluidic emulsification with a Y-shaped microreactor, and a subsequent solvent evaporation method. The flow rate of the dispersed phase (polymer solution) was fixed to 7 µL/min, and 140 or 700 µL/min of the flow rate of the continuous phase (aqueous 0.6 wt % of poly(vinyl alcohol) (PVA) solution) was utilized to produce the dispersion with different diameter. The concentration of dispersed phase was adjusted to 0.1 or 1.0
Language	English
Publishing date	2018-04-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2487261-1
ISSN	1996-1944
ISSN	1996-1944
DOI	10.3390/ma11040582
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