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      Disulfiram suppressed ethanol promoted RANKL-induced osteoclastogenesis in vitro and ethanol-induced osteoporosis in vivo via ALDH1A1-NFATc1 axis

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          Abstract

          Excessive alcohol consumption is positively related to osteoporosis, and its treatment strategies are poorly developed. Disulfiram inhibits receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis; however, whether it can be used for ethanol-induced osteoclastogenesis and its underlying mechanism are still unclear. In this study, we demonstrated that ethanol promoted RANKL-induced osteoclast formation and bone resorption, whereas, disulfiram suppressed ethanol-induced osteoclastogenesis by abrogating the expression of nuclear factor of activated T cell c1 (NFATc1) in vitro. Further analysis revealed that aldehyde dehydrogenase 1A1 (ALDH1A1) is important for the expression of NFATc1, the master regulator of osteoclast differentiation. Furthermore, we showed that disulfiram protected ethanol-induced osteoporosis in vivo. Overall, our study provides promising evidence that disulfiram can be used as a treatment strategy for alcohol-related osteoporosis via the ALDH1A1T–NFATc1 axis.

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          c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling.

          A E Grigoriadis, Z. Wang, M G Cecchini … (1994)
          Mice lacking the proto-oncogene c-fos develop the bone disease osteopetrosis. Fos mutant mice were found to have a block in the differentiation of bone-resorbing osteoclasts that was intrinsic to hematopoietic cells. Bone marrow transplantation rescued the osteopetrosis, and ectopic c-fos expression overcame this differentiation block. The lack of Fos also caused a lineage shift between osteoclasts and macrophages that resulted in increased numbers of bone marrow macrophages. These results identify Fos as a key regulator of osteoclast-macrophage lineage determination in vivo and provide insights into the molecular mechanisms underlying metabolic bone diseases.
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            Regulation of NFATc1 in Osteoclast Differentiation

            Jung Kim, Nacksung Kim (2014)
            Osteoclasts are unique cells that degrade the bone matrix. These large multinucleated cells differentiate from the monocyte/macrophage lineage upon stimulation by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL). Activation of transcription factors such as microphthalmia transcription factor (MITF), c-Fos, NF-κB, and nuclear factor-activated T cells c1 (NFATc1) is required for sufficient osteoclast differentiation. In particular, NFATc1 plays the role of a master transcription regulator of osteoclast differentiation. To date, several mechanisms, including transcription, methylation, ubiquitination, acetylation, and non-coding RNAs, have been shown to regulate expression and activation of NFATc1. In this review, we have summarized the various mechanisms that control NFATc1 regulation during osteoclast differentiation.
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              Requirement for NF-kappaB in osteoclast and B-cell development.

              G Franzoso, L. Carlson, L Xing … (1997)
              NF-kappaB is a family of related, dimeric transcription factors that are readily activated in cells by signals associated with stress or pathogens. These factors are critical to host defense, as demonstrated previously with mice deficient in individual subunits of NF-kappaB. We have generated mice deficient in both the p50 and p52 subunits of NF-kappaB to reveal critical functions that may be shared by these two highly homologous proteins. We now demonstrate that unlike the respective single knockout mice, the p50/p52 double knockout mice fail to generate mature osteoclasts and B cells, apparently because of defects that track with these lineages in adoptive transfer experiments. Furthermore, these mice present markedly impaired thymic and splenic architectures and impaired macrophage functions. The blocks in osteoclast and B-cell maturation were unexpected. Lack of mature osteoclasts caused severe osteopetrosis, a family of diseases characterized by impaired osteoclastic bone resorption. These findings now establish critical roles for NF-kappaB in development and expand its repertoire of roles in the physiology of differentiated hematopoietic cells.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (iso-abbrev): Aging (Albany NY)
                Journal ID (publisher-id): Aging
                Title: Aging (Albany NY)
                Publisher: Impact Journals
                ISSN (Electronic): 1945-4589
                Publication date Collection: 15 October 2019
                Publication date (Electronic): 08 October 2019
                Volume: 11
                Issue: 19
                Pages: 8103-8119
                Affiliations
                [1 ]Department of Orthopaedics, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing), Zhejiang 312000, China
                [2 ]Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 312000, China
                [3 ]Department of Urinary Surgery, Jinhua Central Hospital (Jinhua Hospital, Zhejiang University School of Medicine, Jinhua), Zhejiang 321000, China
                [4 ]Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Yu Qian; email: doctor120@hotmail.com
                Article
                Publisher ID: 102279 Publisher ID: 102279
                DOI: 10.18632/aging.102279
                PMC ID: 6814600
                PubMed ID: 31596733
                SO-VID: 67d0392e-2055-4f7c-9923-946f50473d4b
                Copyright © Copyright © 2019 Jia et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 29 July 2019
                Date accepted : 05 September 2019
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Cell biology
                Keywords: disulfiram,ethanol,aldh1a1,nfatc1,osteoclastogenesis
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: disulfiram, ethanol, aldh1a1, nfatc1, osteoclastogenesis

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