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Bidirectional regulation of bone formation by exogenous and osteosarcoma-derived Sema3A

Authors
  • de Ridder, Daniëlle1
  • Marino, Silvia1
  • Bishop, Ryan T.1
  • Renema, Nathalie2
  • Chenu, Chantal3
  • Heymann, Dominique1, 4
  • Idris, Aymen I.1
  • 1 Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield, S10 2RX, UK , Sheffield (United Kingdom)
  • 2 INSERM, UMR1238, Université de Nantes, Faculty of Medicine, 1 rue Gaston Veil, Nantes cedex 1, 4035, France , Nantes cedex 1 (France)
  • 3 Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UK , London (United Kingdom)
  • 4 INSERM, UMR 1232, Institut de Cancérologie de l’Ouest, Université de Nantes, Bd Jacques Monod, Saint-Herblain, 44805, France , Saint-Herblain (France)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
May 02, 2018
Volume
8
Issue
1
Identifiers
DOI: 10.1038/s41598-018-25290-2
Source
Springer Nature
License
Green

Abstract

Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, increases osteoblast differentiation, stimulates bone formation and enhances fracture healing. Here, we report a previously unknown role of Sema3A in the regulation of ectopic bone formation and osteolysis related to osteosarcoma. Human recombinant (exogenous) Sema3A promoted the expression of osteoblastic phenotype in a panel of human osteosarcoma cell lines and inhibited the ability of these cells to migrate and enhance osteoclastogenesis in vitro. In vivo, administration of exogenous Sema3A in mice after paratibial inoculation of KHOS cells increased bone volume in non-inoculated and tumour-bearing legs. In contrast, Sema3A overexpression reduced the ability of KHOS cells to cause ectopic bone formation in mice and to increase bone nodule formation by engaging DKK1/β-catenin signalling. Thus, Sema3A is of potential therapeutic efficacy in osteosarcoma. However, inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term usefulness as therapeutic agent.

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