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Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα

BACKGROUND: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche, which includes bone-forming and bone-resorbing cells, i.e., osteoblasts (OBs) and osteoclasts (OCs). OBs originate from mesenchymal progenitors, while OCs are derived from HSCs. Self-renewal, proliferation and differen...

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Autores principales: Oppezzo, Alessia, Monney, Lovely, Kilian, Henri, Slimani, Lofti, Maczkowiak-Chartois, Frédérique, Rosselli, Filippo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290407/
https://www.ncbi.nlm.nih.gov/pubmed/37355617
http://dx.doi.org/10.1186/s13578-023-01067-7
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author Oppezzo, Alessia
Monney, Lovely
Kilian, Henri
Slimani, Lofti
Maczkowiak-Chartois, Frédérique
Rosselli, Filippo
author_facet Oppezzo, Alessia
Monney, Lovely
Kilian, Henri
Slimani, Lofti
Maczkowiak-Chartois, Frédérique
Rosselli, Filippo
author_sort Oppezzo, Alessia
collection PubMed
description BACKGROUND: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche, which includes bone-forming and bone-resorbing cells, i.e., osteoblasts (OBs) and osteoclasts (OCs). OBs originate from mesenchymal progenitors, while OCs are derived from HSCs. Self-renewal, proliferation and differentiation of HSCs are under the control of regulatory signals generated by OBs and OCs within the BM niche. Consequently, OBs and OCs control both bone physiology and hematopoiesis. Since the human developmental and bone marrow failure genetic syndrome fanconi anemia (FA) presents with skeletal abnormalities, osteoporosis and HSC impairment, we wanted to test the hypothesis that the main pathological abnormalities of FA could be related to a defect in OC physiology and/or in bone homeostasis. RESULTS: We revealed here that the intrinsic differentiation of OCs from a Fanca(−/−) mouse is impaired in vitro due to overactivation of the p53–p21 axis and defects in NF-kB signaling. The OC differentiation abnormalities observed in vitro were rescued by treating Fanca(−/−) cells with the p53 inhibitor pifithrin-α, by treatment with the proinflammatory cytokine TNFα or by coculturing them with Fanca-proficient or Fanca-deficient osteoblastic cells. CONCLUSIONS: Overall, our results highlight an unappreciated role of Fanca in OC differentiation that is potentially circumvented in vivo by the presence of OBs and TNFα in the BM niche. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01067-7.
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spelling pubmed-102904072023-06-25 Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα Oppezzo, Alessia Monney, Lovely Kilian, Henri Slimani, Lofti Maczkowiak-Chartois, Frédérique Rosselli, Filippo Cell Biosci Research BACKGROUND: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche, which includes bone-forming and bone-resorbing cells, i.e., osteoblasts (OBs) and osteoclasts (OCs). OBs originate from mesenchymal progenitors, while OCs are derived from HSCs. Self-renewal, proliferation and differentiation of HSCs are under the control of regulatory signals generated by OBs and OCs within the BM niche. Consequently, OBs and OCs control both bone physiology and hematopoiesis. Since the human developmental and bone marrow failure genetic syndrome fanconi anemia (FA) presents with skeletal abnormalities, osteoporosis and HSC impairment, we wanted to test the hypothesis that the main pathological abnormalities of FA could be related to a defect in OC physiology and/or in bone homeostasis. RESULTS: We revealed here that the intrinsic differentiation of OCs from a Fanca(−/−) mouse is impaired in vitro due to overactivation of the p53–p21 axis and defects in NF-kB signaling. The OC differentiation abnormalities observed in vitro were rescued by treating Fanca(−/−) cells with the p53 inhibitor pifithrin-α, by treatment with the proinflammatory cytokine TNFα or by coculturing them with Fanca-proficient or Fanca-deficient osteoblastic cells. CONCLUSIONS: Overall, our results highlight an unappreciated role of Fanca in OC differentiation that is potentially circumvented in vivo by the presence of OBs and TNFα in the BM niche. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01067-7. BioMed Central 2023-06-24 /pmc/articles/PMC10290407/ /pubmed/37355617 http://dx.doi.org/10.1186/s13578-023-01067-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Oppezzo, Alessia
Monney, Lovely
Kilian, Henri
Slimani, Lofti
Maczkowiak-Chartois, Frédérique
Rosselli, Filippo
Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα
title Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα
title_full Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα
title_fullStr Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα
title_full_unstemmed Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα
title_short Fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by TNFα
title_sort fanca deficiency is associated with alterations in osteoclastogenesis that are rescued by tnfα
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290407/
https://www.ncbi.nlm.nih.gov/pubmed/37355617
http://dx.doi.org/10.1186/s13578-023-01067-7
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