Disulfiram ameliorates bone loss in ovariectomized mice by suppressing osteoclastogenesis.

Autor: Fukui T; Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan., Terashima A; Bone and Cartilage Regenerative Medicine, The University of Tokyo Hospital, Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. tera-ort@m.u-tokyo.ac.jp., Omata Y; Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.; Bone and Cartilage Regenerative Medicine, The University of Tokyo Hospital, Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan., Chijimatsu R; Bone and Cartilage Regenerative Medicine, The University of Tokyo Hospital, Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.; Center for Comprehensive Genomic Medicine, Okayama University Hospital, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan., Okamoto K; Department of Osteoimmunology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.; Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan., Tsukasaki M; Department of Osteoimmunology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan., Fukuda Y; Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, Chiba, 278-8510, Japan.; Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, Chiba, 278-8510, Japan., Hayata T; Department of Molecular Pharmacology, 2641, Yamazaki, Noda, Chiba, 278-8510, Japan., Saitoh A; Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, Chiba, 278-8510, Japan., Toda E; Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, Chiba, 278-8510, Japan.; Department of Analytic Human Pathology, Nippon Medical School, 1-25-16, Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan., Takayanagi H; Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan., Tanaka S; Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan., Terashima Y; Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, Chiba, 278-8510, Japan., Saito T; Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Jazyk: angličtina
Zdroj: Journal of bone and mineral metabolism [J Bone Miner Metab] 2024 Oct 07. Date of Electronic Publication: 2024 Oct 07.
DOI: 10.1007/s00774-024-01555-x
Abstrakt: Introduction: Disulfiram (DSF), known as an anti-alcoholism drug, has been reported to suppress osteoclast differentiation in vitro; however, it remains uncertain whether DSF is effective in preventing osteoclastogenesis in vivo. This study aimed to investigate the effect of DSF administration in osteoporotic mice and its contribution to osteoclastogenesis in vivo.
Materials and Methods: The bone phenotype of ovariectomized mice, both treated and untreated with DSF, was examined using microcomputed tomography analysis. Osteoclastic and osteoblastic parameters were assessed through bone morphometric analysis. The direct effect of DSF on osteoblastogenesis in vitro was evaluated via a primary osteoblast culture experiment. The expression of genes related to DSF targets (Nup85, Ccr2, and Ccr5) in osteoclast-lineage cells was examined using scRNA-seq analysis and flow cytometry analysis using the bone marrow cells from ovariectomized mice. The impact of DSF on osteoclast-lineage cells was assessed using primary cultures of osteoclasts.
Results: DSF administration ameliorated ovariectomy-induced bone loss and mitigated the increase of osteoclasts without affecting osteoblastogenesis. The scRNA-seq data revealed that osteoclast precursor cells expressed Nup85, Ccr2, and Ccr5. CCR2 and CCR5-positive cells in osteoclast precursor cells within bone marrow increased following ovariectomy, and this increase was canceled by DSF administration. Finally, we found that DSF had a significant inhibitory effect on osteoclastogenesis in the early stage by suppressing Tnfrsf11a expression.
Conclusion: This study demonstrates that DSF could be a candidate for osteoporosis therapies because it suppresses osteoclastogenesis from an early stage in vivo.
(© 2024. The Author(s).)
Databáze: MEDLINE
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